Tuesday, December 23, 2008

The genetics of skin pigmentation in beach mice from different beaches

A similar story to humans in East Asia and Europe...

The Genetic Basis of Phenotypic Convergence in Beach Mice: Similar Pigment Patterns but Different Genes Cynthia C. Steiner, Holger Römpler, Linda M. Boettger, Torsten Schöneberg and Hopi E. Hoekstra
Molecular Biology and Evolution 2009 26(1):35-45
Abstract: Convergent evolution is a widespread phenomenon seen in diverse organisms inhabiting similar selective environments. However, it is unclear if similar phenotypes are produced by the same or different genes and mutations. Here we analyze the molecular mechanisms underlying convergent pigment pattern among subspecies of the beach mouse (Peromyscus polionotus) inhabiting the Gulf and Atlantic coasts of Florida. In these two geographic regions, separated by more than 300 km, "beach mice" have lighter colored coats than do their mainland counterparts, produced by natural selection for camouflage against the pale coastal sand dunes. We measured color pattern in eight beach mouse subspecies and showed that three of the Gulf Coast subspecies are more phenotypically similar to an Atlantic coast subspecies than to their Gulf Coast neighbors. However, light-colored beach mice do not form a monophyletic group. Previous results implicated a single derived amino acid change in the melanocortin-1 receptor (Mc1r) as a major contributor to pigment pattern in the Gulf Coast beach mice; despite phenotypic similarities, the derived Mc1r allele was not found in the Atlantic coast beach mouse populations. Here we show that Atlantic coast beach mice have high levels of Mc1r polymorphism but they lack unique alleles. Functional assays revealed that single amino acid mutations segregating in Atlantic coast beach mice do not cause any change in Mc1r activity compared with the activity of Mc1r from dark-colored mice. These joint results show that convergent pigment patterns in recently diverged beach mouse subspecies—whose developmental constraints are presumably similar—have evolved through a diversity of genetic mechanisms.

Thursday, December 11, 2008

Tradeoff between pathogen resistance and auto-immune response?

I first read about this in one of the earlier papers on European genetic structure where they mention: "a north/south gradient in the incidence of autoimmune diseases has been noted for several continents," and give a reference to this paper which, if I remember correctly, shows differences in incidence of various diseases across Europe and discusses the potential tradeoff between pathogen resistance and auto-immune disorders.

Dan at Genetic Future points out a recent study where they find that the same genetic factors contribute to both celiac disease and type I diabetes (both auto-immune disorders). The study also finds that those with the delta-32 variant of CCR5 (protective of HIV infection) have a lower risk of type I diabetes and celiac disease.
These findings beg the questions: Given the distribution of these diseases across Europe, shouldn't they have controlled for ancestry stratification?, and more generally: Is there a unifying phenotype that can be measured which maps to the underlying factor contributing to all these auto-immune diseases? Why is this phenotype seemingly more prevalent among Northern Europeans? Is there some kind of tradeoff between between pathogen resistance and auto-immune "disorders"?
I must say I'm still unclear about the evidence, if any, for this tradeoff.

Wednesday, December 10, 2008

Slavery, fetal programming, and low birth weight among African Americans

It doesn't look like any hypotheses are tested here. The proposal is not too surprising, but I think it's very important to fully consider it as we try to grasp the complete etiology of health disparities.

Low birth weight of contemporary African Americans: An intergenerational effect of slavery?

Grazyna Jasienska
American Journal of Human Biology 2008, 21: 16 - 24
Abstract: The average birth weight in the contemporary African-American population is about 250 g lower than the average birth weight of European Americans. Differences in genetic and socioeconomic factors present between these two groups can explain only part of birth weight variation. I propose a hypothesis that the low birth weight of contemporary African Americans not only results from the difference in present exposure to lifestyle factors known to affect fetal development but also from conditions experienced during the period of slavery. Slaves had poor nutritional status during all stages of life because of the inadequate dietary intake accompanied by high energetic costs of physical work and infectious diseases. The concept of fetal programming suggests that physiology and metabolism including growth and fat accumulation of the developing fetus, and, thus its birth weight, depend on intergenerational signal of environmental quality passed through generations of matrilinear ancestors. I suggest that several generations that have passed since the abolition of slavery in the United States (1865) has not been enough to obliterate the impact of slavery on the current biological and health condition of the African-American population.

Distance from Africa explains within-population cranial variation better than climate

This paper is somewhat disappointingly deceptive (as Dienekes points out nicely). They are actually looking at within-population variation in cranial traits and how it varies across the globe. They could have put that in their title.
To be fair, I haven't looked too closely at the paper, and it does look interesting and informative as to the relative roles of demographic vs. selection forces in shaping within-population variation.

Distance from Africa, not climate explains human variation.
Lia Betti, François Balloux, William Amos, Tsunehiko Hanihara, Andrea Manica
Proc Roy Soc B Early online
Abstract: The relative importance of ancient demography and climate in determining worldwide patterns of human within-population phenotypic diversity is still open to debate. Several morphometric traits have been argued to be under selection by climatic factors, but it is unclear whether climate affects the global decline in morphological diversity with increasing geographical distance from sub-Saharan Africa. Using a large database of male and female skull measurements, we apply an explicit framework to quantify the relative role of climate and distance from Africa. We show that distance from sub-Saharan Africa is the sole determinant of human within-population phenotypic diversity, while climate plays no role. By selecting the most informative set of traits, it was possible to explain over half of the worldwide variation in phenotypic diversity. These results mirror those previously obtained for genetic markers and show that ‘bones and molecules’ are in perfect agreement for humans.

Thursday, December 04, 2008

European ancestry associated with higher breast cancer risk?

Latinas have been found to have a lower incidence of breast cancer than other ethnic groups. Indigenous Americans have the lowest incidence. This meta-review paper from a few months ago finds that ethnic disparities in breast cancer can be explained by SES, except for the lower incidence among African Americans.

So what do they find in this new paper (see abstract below)? It's a case control study with a pretty large sample size (440 cases and 597 controls, matched for age) of Latinas in the SF Bay area to determine whether genetic differences between groups account for differences in breast cancer incidence. They used 106 AIMs (ancestry informative markers). Interestingly:
"Breast cancer among Latinas presents a particularly
interesting case because the main ancestral components of the Latino population (European and Indigenous American) have the highest and lowest breast cancer incidence (1)."
They control for a suite of known breast cancer risk factors
(including education, but unfortunately, not income). Surprisingly the cases and controls differed significantly for many of the measured risk factors.

The main findings:
"In unadjusted models, we found a strong association between genetic ancestry (continuous) and breast cancer risk. Higher European ancestry was associated with increased risk, with an odds ratio (OR) of 1.79 [95% confidence intervals (95% CI), 1.28–2.79; P less than 0.001] for every 25% increase in European ancestry. When known risk factors and place of birth were adjusted for (Table 2), the association with European ancestry was somewhat attenuated but remained statistically significant (OR, 1.39; 95% CI, 1.06–2.11; P = 0.013). When African ancestry was included in the adjusted model, the association with European ancestry became stronger [OR for European ancestry, 1.54 (95% CI, 1.11–2.52; P = 0.004), and OR for African ancestry, 2.05 (95% CI, 1.00–7.56; P = 0.055)]."
They also looked at the association using genetic admixture and "using parent/grandparent European origin instead of genetic ancestry."
"We observed a significant association between the number of European-born parents/grandparents and breast cancer risk, with higher number of European ancestors being associated with increased risk (OR, 1.21; 95% CI, 1.02–1.44; P = 0.025, adjusted model)."
Although their results suggest that there may be some genetic risk factor specific to individuals with higher European ancestry, they are careful to acknowledge the possibility for residual confounders. It's too bad they didn't control for income and/or some other SES variables.

Genetic Ancestry and Risk of Breast Cancer among U.S. Latinas
Laura Fejerman, Esther M. John, Scott Huntsman, Kenny Beckman, Shweta Choudhry, Eliseo Perez-Stable, Esteban González Burchard and Elad Ziv
Cancer Research 2008;68(23):9723–8
Abstract: U.S. Latinas have a lower incidence of breast cancer compared with non-Latina White women. This difference is partially explained by differences in the prevalence of known risk factors. Genetic factors may also contribute to this difference in incidence. Latinas are an admixed population with most of their genetic ancestry from Europeans and Indigenous Americans. We used genetic markers to estimate the ancestry of Latina breast cancer cases and controls and assessed the association with genetic ancestry, adjusting for reproductive and other risk factors. We typed a set of 106 ancestry informative markers in 440 Latina women with breast cancer and 597 Latina controls from the San Francisco Bay area and estimated genetic ancestry using a maximum likelihood method. Odds ratios (OR) and 95% confidence intervals (95% CI) for ancestry modeled as a continuous variable were estimated using logistic regression with known risk factors included as covariates. Higher European ancestry was associated with increased breast cancer risk. The OR for a 25% increase in European ancestry was 1.79 (95% CI, 1.28–2.79; P less than 0.001). When known risk factors and place of birth were adjusted for, the association with European ancestry was attenuated but remained statistically significant (OR, 1.39; 95% CI, 1.06–2.11; P = 0.013). Further work is needed to determine if the association is due to genetic differences between populations or possibly due to environmental factors not measured.

Wednesday, December 03, 2008

Paralogous genes and disease alleles

I don't quite fully get this, but the point of the method that they propose is to look at paralogous genes to more efficiently pinpoint the actual causal variants from among the many "hits" that pop up in GWASs.

Genome-Wide Analysis of Human Disease Alleles Reveals That Their Locations Are Correlated in Paralogous Proteins
Mark Yandell, Barry Moore, Fidel Salas, Chris Mungall, Andrew MacBride, Charles White, Martin G. Reese
PLoS Comput Biol 4(11): e1000218
Abstract: The millions of mutations and polymorphisms that occur in human populations are potential predictors of disease, of our reactions to drugs, of predisposition to microbial infections, and of age-related conditions such as impaired brain and cardiovascular functions. However, predicting the phenotypic consequences and eventual clinical significance of a sequence variant is not an easy task. Computational approaches have found perturbation of conserved amino acids to be a useful criterion for identifying variants likely to have phenotypic consequences. To our knowledge, however, no study to date has explored the potential of variants that occur at homologous positions within paralogous human proteins as a means of identifying polymorphisms with likely phenotypic consequences. In order to investigate the potential of this approach, we have assembled a unique collection of known disease-causing variants from OMIM and the Human Genome Mutation Database (HGMD) and used them to identify and characterize pairs of sequence variants that occur at homologous positions within paralogous human proteins. Our analyses demonstrate that the locations of variants are correlated in paralogous proteins. Moreover, if one member of a variant-pair is disease-causing, its partner is likely to be disease-causing as well. Thus, information about variant-pairs can be used to identify potentially disease-causing variants, extend existing procedures for polymorphism prioritization, and provide a suite of candidates for further diagnostic and therapeutic purposes.

Sunday, November 30, 2008

NY Times article on testing kids for ACTN3 gene

It was only a matter of time, but there is now a company in the US that is offering a test to determine a person's ACTN3 genotype. This is a locus for which there is some evidence of an association with muscle fiber composition (fast vs. slow twitch) and whether an elite athlete competes in sprint or endurance events.
This article in the New York Times describes the test, some of the evidence concerning the association, and some of the issues surrounding its costs/benefits.
My favorite line:
Dr. Foster suggested another way to determine if a child will be good at sprint and power sports. “Just line them up with their classmates for a race and see which ones are the fastest,” he said.
Dan MacArthur has done some of the primary work on this locus and its association with athletic performance. I'm surprised his name didn't show up in the article. Actually, I just noticed that he has also written a blog post about this article.
He discusses the tests' limitations and mentions that this test has been commercially offered in several countries for some time and is available through the personal genomics companies in the US.

There are indeed many limitations to this test. Given what goes into making a great athlete, I see no use for it whatsoever, except for giving some solace to a person wondering why, after years of training, he/she didn't become the great athlete he/she hoped to become. Given the predictive power of this test, I think that the costs (mostly psychological) of doing this test to see what you would be good at greatly outweigh the benefits.

Thursday, November 27, 2008

GWAS of metabolite profiles

This is great, and somewhat appropriate for Thanksgiving.

An important issue in deciphering the genetic basis for traits is appropriate phenotype definition. In this study, they look at the association between metabolic by-products in individuals and their genetic profile. These metabolites represent a better phenotype since they are more proximal to the genetic/biochemical pathways that happen within cells, compared to the clinically assessed symptoms of a "disease." Not only does this give us a more appropriate and well-defined phenotype, it's also a phenotype that can be measured on a continuous scale.

The subjects are from Germany and they briefly dismiss the possibility of population stratification: "Also, recent experimental assessment has found little population stratification to exist within and across Germany [33]". Ironically, the latest European genetic structure study, see my last blog post, showed some stratification within Germany - granted, probably not too big of a deal for this study, but it's just funny

Blood samples were obtained in the morning after overnight fasting. In the future, I can imagine collecting samples after feeding of some sugary or fatty meal to get even better measures of metabolic variation.

Genetics Meets Metabolomics: A Genome-Wide Association Study of Metabolite Profiles in Human Serum.
Gieger C, Geistlinger L, Altmaier E, Hrabe´ de Angelis M, Kronenberg F, et al.
PLoS Genet (2008)4(11): e1000282. doi:10.1371/journal.pgen.1000282
Abstract: The rapidly evolving field of metabolomics aims at comprehensive measurement of ideally all endogenous metabolites in a cell or body fluid. It thereby provides a functional readout of the physiological state of the human body. Genetic variants that associate with changes in the homeostasis of key lipids, carbohydrates, or amino acids are not only expected to display much larger effect sizes due to their direct involvement in metabolite conversion modification, but should also provide access to the biochemical context of such variations, in particular when enzyme coding genes are concerned. To test this hypothesis, we conducted what is, to the best of our knowledge, the first GWA study with metabolomics based on the quantitative measurement of 363 metabolites in serum of 284 male participants of the KORA study. We found associations of frequent single nucleotide polymorphisms (SNPs) with considerable differences in the metabolic homeostasis of the human body, explaining up to 12% of the observed variance. Using ratios of certain metabolite concentrations as a proxy for enzymatic activity, up to 28% of the variance can be explained (p-values 10216 to 10221). We identified four genetic variants in genes coding for enzymes (FADS1, LIPC, SCAD, MCAD) where the corresponding metabolic phenotype (metabotype) clearly matches the biochemical pathways in which these enzymes are active. Our results suggest that common genetic polymorphisms induce major differentiations in the metabolic make-up of the human population. This may lead to a novel approach to personalized health care based on a combination of genotyping and metabolic characterization. These genetically determined metabotypes may subscribe the risk for a certain medical phenotype, the response to a given drug treatment, or the reaction to a nutritional intervention or environmental challenge.

Wednesday, November 26, 2008

European genetic structure, study du jour

Yet another one.
As usual, Dienekes and Razib have talked about this one on their blogs.

Anything new or particularly interesting?
  • within-Germany resolution (see figure, labeled by Razib)
  • big sample, of nearly 6000
  • LCT (lactase), HERC2 (eye color and hair color) and HLA (immune function) regions stood out as most highly correlated to the North-South gradient.
  • they frame the importance of this in relation to picking appropriately matched controls in case-control studies
Ethnicity/country origin of subjects is taken as where the sample was obtained. This is unfortunate since more detailed information on the origin of each subject could have enabled better resolution.

Tuesday, November 25, 2008

Do big brains call for special milk?

Apparently not...
I can't believe no one has already studied this.

Evolutionary modifications of human milk composition: evidence from long-chain polyunsaturated fatty acid composition of anthropoid milks
Lauren A. Milligan and Richard P. Bazinet
Journal of Human Evolution 55: 6, December 2008, 1086-1095
Abstract: Brain growth in mammals is associated with increased accretion of long-chain polyunsaturated fatty acids (LCPUFA) in brain phospholipids. The period of maximum accumulation is during the brain growth spurt. Humans have a perinatal brain growth spurt, selectively accumulating docosahexaenoic acid (DHA) and other LCPUFA from the third trimester through the second year of life. The emphasis on rapid postnatal brain growth and LCPUFA transfer during lactation has led to the suggestion that human milk LCPUFA composition may be unique. Our study tests this hypothesis by determining fatty acid composition for 11 species of captive anthropoids (n = 53; Callithrix jacchus, Cebus apella, Gorilla gorilla, Hylobates lar, Leontopithecus rosalia, Macaca mulatta, Pan troglodytes, Pan paniscus, Pongo pygmaeus, Saimiri boliviensis, and Symphalangus syndactylus). Results are compared to previously published data on five species of wild anthropoids (n = 28; Alouatta paliatta, Callithrix jacchus, Gorilla beringei, Leontopithecus rosalia, and Macaca sinica) and human milk fatty acid profiles. Milk LCPUFA profiles of captive anthropoids (consuming diets with a preformed source of DHA) are similar to milk from women on a Western diet, and those of wild anthropoids are similar to milk from vegan women. Collectively, the range of DHA percent composition values from nonhuman anthropoid milks (0.03–1.1) is nearly identical to that from a cross-cultural analysis of human milk (0.06–1.4). Humans do not appear to be unique in their ability to secrete LCPUFA in milk but may be unique in their access to dietary LCPUFA.

Determining the genetic composition of an unknown founder population

Using the HLA system, they describe a method to determine the haplotypes of an unknown founder population given information on the haplotypes of the admixed population and those of the other founder population.

Re-creation of the genetic composition of a founder population.
Klitz W, Maiers M, Gragert L.
Human Genetics 2008 Nov;124(4):417-21.
Abstract: Human ethnic groups are frequently comprised of two or more founder populations. One of these founding populations is often available for contemporary sampling. We describe a method for reconstructing the composition of a missing founder population using the highly informative haplotypes comprising the HLA system. An application of the method is demonstrated using bone marrow registry samples of African Americans. We use contemporary samples of African Americans and European Americans to derive haplotypes of the West African founder populations. This approach may also be useful for reconstructing ancestral haplotypes for regions elsewhere in the genome.

Wednesday, November 19, 2008

Review paper on the importance of considering sex for genotype-phenotype relationships

Sex-specific genetic architecture of human disease
Carole Ober, Dagan A. Loisel & Yoav Gilad
Nature Reviews Genetics 9, 911-922 (December 2008)
Abstract: Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.

Friday, November 14, 2008

Demonstration of epigenetic changes due to early stress, and how do you measure methylation?

An interesting paper showing epigenetic changes caused by early stress has recently come out in PNAS (see below). Siblings who were in utero during the Dutch Famine in the winter of '44 - '45 had less methylation on the IGF2 gene compared to their same-sex siblings who were not in utero during the famine.

So, how exactly does one measure methylation?
According to the paper, and a Wikipedia entry:
First, methylation usually occurs on CpG cytosines, and when you treat your piece of DNA with bisulfite, the methylated cytosines becomes reduced to uracil. Then a variety of PCR methods and/or sequencing methods can be applied. In this paper they use a mass-spectroscopy based method called Epityper.

Persistent epigenetic differences associated with prenatal exposure to famine in humans
Bastiaan T. Heijmansa, Elmar W. Tobia, Aryeh D. Stein, Hein Putter, Gerard J. Blauw, Ezra S. Susser, P. Eline Slagboom, and L. H. Lumeye
PNAS 2008 105:17046-17049
Abstract: Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944–45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.

Updated refresher course on genes

There's an article in the NYT by Carl Zimmer called "Now: The Rest of the Genome" that discusses some of the new findings about how genes work:
Here are some of the more interesting nuggets:
  • "the average protein-coding region produces 5.7 different transcripts"
  • "cells often toss exons into transcripts from other genes. Those exons may come from distant locations, even from different chromosomes."
  • "When an embryo begins to develop, the epigenetic marks that have accumulated on both parents’ DNA are stripped away. The cells add a fresh set of epigenetic marks in the same pattern that its parents had when they were embryos."
  • "As an embryo matures, epigenetic marks in different cells are altered, and as a result they develop into different tissues. Once the final pattern of epigenetic marks is laid down, it clings stubbornly to cells. When cells divide, their descendants carry the same set of marks."
  • "Although only 1.2 percent of the human genome encodes proteins, the Encode scientists estimate that a staggering 93 percent of the genome produces RNA transcripts."
  • "Dr. Prohaska argues that a gene should be the smallest unit underlying inherited traits. It may include not just a collection of exons, but the epigenetic marks on them that are inherited as well."

Monday, November 10, 2008

Facilitated Variation: How the genetic code hedges its bets on a variable environment

Haven't had the chance to look very closely at the details, but this paper looks very interesting. Evolution thrives on variation, and according to them, the genomes of organisms can accumulate a sort of stored memory of past adaptation to varying environments that as they say "makes it more likely that random genetic changes will result in organisms with novel shapes that can survive."

Facilitated Variation: How Evolution Learns from Past Environments To Generalize to New Environments
Merav Parter, Nadav Kashtan, Uri Alon
PLoS Comput Biol 4(11): e1000206.
Abstract: One of the striking features of evolution is the appearance of novel structures in organisms. Recently, Kirschner and Gerhart have integrated discoveries in evolution, genetics, and developmental biology to form a theory of facilitated variation (FV). The key observation is that organisms are designed such that random genetic changes are channeled in phenotypic directions that are potentially useful. An open question is how FV spontaneously emerges during evolution. Here, we address this by means of computer simulations of two well-studied model systems, logic circuits and RNA secondary structure. We find that evolution of FV is enhanced in environments that change from time to time in a systematic way: the varying environments are made of the same set of subgoals but in different combinations. We find that organisms that evolve under such varying goals not only remember their history but also generalize to future environments, exhibiting high adaptability to novel goals. Rapid adaptation is seen to goals composed of the same subgoals in novel combinations, and to goals where one of the subgoals was never seen in the history of the organism. The mechanisms for such enhanced generation of novelty (generalization) are analyzed, as is the way that organisms store information in their genomes about their past environments. Elements of facilitated variation theory, such as weak regulatory linkage, modularity, and reduced pleiotropy of mutations, evolve spontaneously under these conditions. Thus, environments that change in a systematic, modular fashion seem to promote facilitated variation and allow evolution to generalize to novel conditions.

Wednesday, November 05, 2008

Post-admixture selection among Mexican Americans?

This paper examines the variation in admixture proportions across the genome at 284 microsatellite markers among 392 Mexican Americans. They find increased European ancestry on a region of chromosome 1, and decreased African ancestry on Chromosomes 2 and 9 (see figure on right: "Genome-wide distribution of African (bottom line), European (top line) and Native American (middle line) ancestry. The dashed vertical lines correspond to chromosome boundaries. Chromosomes are listed in numerical order from 1 to 22")
Since the markers are widely spaced out, they couldn't pinpoint any specific genes. Interestingly, these results differ pretty dramatically compared to a previous similar study among Puerto Ricans. Also, interestingly, since they had people who were hypertensive or had diabetes, and people who didn't, they were able to determine that the identified regions were not associated with these health outcomes, since the local ancestry at those areas was no different between cases and controls.
They do make some mention at the end that they might expect selection at infectious-disease related genes given that the ancestral parental populations that had adapted to specific environments were suddenly faced with different environments.

Genome-wide distribution of ancestry in Mexican Americans
Analabha Basu, Hua Tang, Xiaofeng Zhu, C. Charles Gu, Craig Hanis, Eric Boerwinkle and Neil Risch
Human Genetics Volume 124, Number 3 / October, 2008
Abstract Migrations to the new world brought together individuals from Europe, Africa and the Americans. Inter-mating between these migrant and indigenous populations led to the subsequent formation of new admixed populations, such as African and Latino Americans. These unprecedented events brought together genomes that had evolved independently on different continents for tens of thousands of years and presented new environmental challenges for the indigenous and migrant populations, as well as their offspring. These circumstances provided novel opportunities for natural selection to occur that could be reflected in deviations at specific locations from the genome-wide ancestry distribution. Here we present an analysis examining European, Native American and African ancestry based on 284 microsatellite markers in a study of Mexican Americans from the Family Blood Pressure Program. We identified two genomic regions where there was a significant decrement in African ancestry (at 2p25.1, p less than 10−8 and 9p24.1, p less than 2 × 10−5) and one region with a significant increase in European ancestry (at 1p33, p less than 2 × 10−5). These locations may harbor genes that have been subjected to natural selection after the ancestral mixing giving rise to Mexicans.

Sunday, November 02, 2008

Another EDAR - hair thickness association study

A SNP in EDAR has been found to be associated with hair thickness among SE Asians and increased expression of this gene results in mice with thicker hair (via p-ter at GNXP). This study looks at the association among a Japanese sample and compare it to the Southeast Asian sample. Interestingly, there are considerable differences in hair thickness between Japanese and Southeast Asians:
"JPN individuals have more than 30% larger mean cross-sectional area (6,518 'units') than SEA (4,957 'units') and more than 50% larger than Africans (4,274 'units') and Caucasians (3,857 'units') (12)."
Since population origin also explains variation in hair thickness, the EDAR SNP "1540T/C by itself cannot explain all the differentiation of hair fiber thickness between JPN and SEA" and other genetic and environmental factors must be responsible.

They do a control for population stratification, but it would have been interesting to see a STRUCTURE output of their sample. I assume there wasn't that much stratification in terms of the 23 markers that they chose to look at (those with high 'JPN+CHN vs. the rest of the HapMap pops' differentiation)

A replication study confirmed the EDAR gene to be a major contributor to population differentiation regarding head hair thickness in Asia
Akihiro Fujimoto, Jun Ohashi, Nao Nishida, Taku Miyagawa, Yasuyuki Morishita, Tatsuhiko Tsunoda, Ryosuke Kimura and Katsushi Tokunaga
Human Genetics
V. 124, Number 2 / September, 2008
Abstract Hair morphology is a highly divergent phenotype among human populations. We recently reported that a nonsynonymous SNP in the ectodysplasin A receptor (EDAR 1540T/C) is associated with head hair fiber thickness in an ethnic group in Thailand (Thai-Mai) and an Indonesian population. However, these Southeast Asian populations are genetically and geographically close, and thus the genetic contribution of EDAR to hair morphological variation in the other Asian populations has remained unclear. In this study, we examined the association of 1540T/C with hair morphology in a Japanese population (Northeast Asian). As observed in our previous study, 1540T/C showed a significant association with hair cross-sectional area (P = 2.7 × 10−6) in Japanese. When all populations (Thai-Mai, Indonesian, and Japanese) were combined, the association of 1540T/C was stronger (P = 3.8 × 10−10) than those of age, sex, and population. These results indicate that EDAR is the genetic determinant of hair thickness as well as a strong contributor to hair fiber thickness variation among Asian populations.

Saturday, November 01, 2008

Gene-language co-evolution in Melanesia

This paper, authored by fellow UNM anthropologists, looks at the nature of the relationship between genetic and linguistic variation in Melanesia.
Kambiz and Razib have both commented on this paper.

Genetic and Linguistic Coevolution in Northern Island Melanesia

Keith Hunley, Michael Dunn, Eva Lindström, Ger Reesink, Angela Terrill, Meghan E. Healy, George Koki, Françoise R. Friedlaender, Jonathan S. Friedlaender
PLoS Genetics
Abstract: Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isolation at the time of early range expansions into the region. The second is analogous to the genetic model of isolation by distance, and it predicts that genetic and linguistic correspondences formed through continuing genetic and linguistic exchange between neighboring populations. We tested the predictions of the two models by comparing observed and simulated patterns of genetic variation, genetic and linguistic trees, and matrices of genetic, linguistic, and geographic distances. The data consist of 751 autosomal microsatellites and 108 structural linguistic features collected from 33 Northern Island Melanesian populations. The results of the tests indicate that linguistic and genetic exchange have erased any evidence of a splitting and isolation process that might have occurred early in the settlement history of the region. The correlation patterns are also inconsistent with the predictions of the isolation by distance coevolutionary process in the larger Northern Island Melanesian region, but there is strong evidence for the process in the rugged interior of the largest island in the region (New Britain). There we found some of the strongest recorded correlations between genetic, linguistic, and geographic distances. We also found that, throughout the region, linguistic features have generally been less likely to diffuse across population boundaries than genes. The results from our study, based on exceptionally fine-grained data, show that local genetic and linguistic exchange are likely to obscure evidence of the early history of a region, and that language barriers do not particularly hinder genetic exchange. In contrast, global patterns may emphasize more ancient demographic events, including population splits associated with the early colonization of major world regions.

Friday, October 31, 2008

Evolutionary perspective on the genetics of osteoporosis

This review paper in Human Genetics discusses osteoporosis from an evolutionary and genetic perspective, and sometimes reads like a list of personal health guidelines (which is ok, I guess). I'm usually pretty reserved when it comes to criticizing papers on my blog, but I'm going to make an exception and say that this paper was somewhat disappointing, especially given that it was published in a high level journal: Human Genetics.
Ok, so first the obligatory point about how we are "stone age bodies living in a novel, modern world":
" ... current demographic trends will have the effect of altering what was once a positive adaptation for distinctive human bipedality into a serious set of “collateral” pathology among the modern elderly (Latimer 2005)."
...then a brief mention on the source of population differences: (I don't like the "Africans" generalization)
"Therefore, Africans more frequently have lactose intolerance, probably because they do not need as much vitamin D and calcium to maintain their (relatively strong) skeletons. On the contrary, skin depigmentation and high consumption of dairy products do not seem to protect Northern Europeans from fractures."
They also go on to explain the mechanism by which consumption of whole grain and milk products likely aggravates the risk of osteoporosis, which is pretty interesting.

He then briefly moves on to the genetics of osteoporosis with this statement which I find a bit hard to swallow, maybe just because I'm a too much of a hard-core adaptationist:
"It seems accurate to assume that if osteoporosis has a genetic determinant, its genetics will share peculiarity with the aging per se, being an example of “post-reproductive” genetics (Capri et al. 2008), which is difficult to explain by a selection process."
He argues that there would have been no selection against osteoporotic phenotypes since these cause problems later in life and would have no effect early in life, an argument which leaves me unconvinced:
"Therefore, children with a “pro-osteoporotic” bone architecture and lower bone mineralization were not selected against—which means, they were able to transfer their genes further on."
At the end of the paper are statements about the future of evolution in humans (which generally make me cringe):
"Is natural selection still a driving force in humans, given that our survival is often less dependent on genes than on technology?"
Osteoporosis: an evolutionary perspective
David Karasik
Human Genetics early online
Abstract: Increased life expectancy has led to an overall aging of the population and greater numbers of elderly people. Therefore, the number of people with osteoporosis has increased substantially, accompanied with an epidemic of hip fractures. Osteoporosis is an age-related systemic condition that naturally occurs, among mammals, only in humans. Osteoporosis is known to be highly heritable. However, assuming a genetic determinant for this post-reproductive disease to be transmitted from one generation to the next is counter-intuitive, based on the principles of human evolution, I will attempt to provide an explanation of the phenomenon from the point of view of evolution, selection, and changed environment in humans, which contributed to human longevity, while on other hand, contribute to diseases of civilization, including osteoporosis. There is a need to delve into evolution of human species in search for adaptive patterns to a specific environment that humans are operating in the last couple of millennia, to clarify whether “good” and “bad” genes exist, and how to find and correct them. The answer to the above questions will help us to identify causes of the current epidemic of osteoporosis and to pin-point a tailored treatment.

Tuesday, October 28, 2008

Predicting unobserved phenotypes from genotypic data

This looks really interesting. The goal is to use whole genome SNP data to predict three phenotypes in mice (coal color, % of CD8+ cells, cellular hemoglobin), using "reversible jump MCMC". According to this website this is how RJMCMC works:
"– RJMCMC randomly “walks around” the space of possible model structures by changing one edge at a time – called structurallearning.
– At each step in its “walk”, all of the model parameters are updated
– called parametrical learning.
– At the end, you have a list of all of the model structures it visited at each step and their corresponding set of parameters."
They cite this recent paper that I posted about a few months ago that proposes a different way of looking simultaneously at the association between a collection of SNPs and some trait.
So, in this paper, they seem to be able to make decent predictions about these traits using about 12,000 SNPs in each of 2,300 mice. The correlations between observed and expexted phenotypes, using only genotype data, are in the range of .33 to .85.
There's really a lot of interesting things in this paper and I don't have to go over all of them.
I'll just end by mentioning that, as the authors state, if we were to do this in humans we would probably need many more markers and more individuals since the mice used in this experiment were from inbred lines with extended LD.

Predicting Unobserved Phenotypes for Complex Traits from Whole-Genome SNP Data
Sang Hong Lee, Julius H. J. van der Werf, Ben J. Hayes, Michael E. Goddard, Peter M. Visscher
PLoS Genet 4(10): e1000231.
Abstract: Genome-wide association studies (GWAS) for quantitative traits and disease in humans and other species have shown that there are many loci that contribute to the observed resemblance between relatives. GWAS to date have mostly focussed on discovery of genes or regulatory regions habouring causative polymorphisms, using single SNP analyses and setting stringent type-I error rates. Genome-wide marker data can also be used to predict genetic values and therefore predict phenotypes. Here, we propose a Bayesian method that utilises all marker data simultaneously to predict phenotypes. We apply the method to three traits: coat colour, %CD8 cells, and mean cell haemoglobin, measured in a heterogeneous stock mouse population. We find that a model that contains both additive and dominance effects, estimated from genome-wide marker data, is successful in predicting unobserved phenotypes and is significantly better than a prediction based upon the phenotypes of close relatives. Correlations between predicted and actual phenotypes were in the range of 0.4 to 0.9 when half of the number of families was used to estimate effects and the other half for prediction. Posterior probabilities of SNPs being associated with coat colour were high for regions that are known to contain loci for this trait. The prediction of phenotypes using large samples, high-density SNP data, and appropriate statistical methodology is feasible and can be applied in human medicine, forensics, or artificial selection programs.

Friday, October 24, 2008

Another study on European genetic structure

...this time focused on Northern Europe, and especially Finland, using 250,000 SNPs, STRUCTURE, MDS plots and other measures of population differentiation.
see Dienekes' post for STRUCTURE output, and other comments.

Wednesday, October 22, 2008

I wanted to do this!! - Eating behavior at Chinese buffets

Dang!!, I've always wanted to do a study like this, but these researchers beat me to the punch. The things they look at here are pretty interesting (and frankly, pretty funny), but they could have looked at the types of foods people were eating (ex: meat vs. other), SES, ethnicity etc.... Of course that would entail more complicated data collection... This reminds me of this great study.

Eating behavior and obesity at Chinese buffets.
Wansink B, Payne CR.
Obesity 2008 Aug;16(8):1957-60.
Abstract: The aim of this study was to investigate whether the eating behaviors of people at all-you-can-eat Chinese buffets differs depending upon their body mass. The resulting findings could confirm or disconfirm previous laboratory research that has been criticized for being artificial. METHODS AND PROCEDURES: Trained observers recorded the height, weight, sex, age, and behavior of 213 patrons at Chinese all-you-can-eat restaurants. Various seating, serving, and eating behaviors were then compared across BMI levels. RESULTS: Patrons with higher levels of BMI were more likely to be associated with using larger plates vs. smaller plates (OR 1.16, P less than 0.01) and facing the buffet vs. side or back (OR 1.10, P less than 0.001). Patrons with higher levels of BMI were less likely to be associated with using chopsticks vs. forks (OR 0.90,P less than 0.05), browsing the buffet before eating vs. serving themselves immediately (OR 0.92, P less than 0.001), and having a napkin on their lap vs. not having a napkin on their lap (OR 0.92, P less than 0.01). Patrons with lower BMIs left more food on their plates (10.6% vs. 6.0%, P less than 0.05) and chewed more per bite of food (14.8 vs. 11.9, P less than 0.001). DISCUSSION: These observational findings of real-world behavior provide support for laboratory studies that have otherwise been dismissed as artificial.

Tuesday, October 21, 2008

Hispanics and Alzheimer's: article in New York Times

It looks like Hispanics have a disproportionately high prevalence of Alzheimer's and tend to develop it earlier, according to research cited in this New York Times article.
Genetic reasons are not favored, at least according to what the author of the article, Pam Belluck has gleaned:
"It is not that Hispanics are more genetically predisposed to Alzheimer’s, say experts, who say the diversity of ethnicities that make up Hispanics or Latinos make a genetic explanation unlikely."
...and what this researcher has found:
Dr. Rafael A. Lantigua, a professor of clinical medicine at Columbia University Medical School, said, “There’s no gene at this point that we can say this is just for Latinos.” Dr. Lantigua added that one gene that increased Alzheimer’s risk was less prevalent in Latinos than non-Hispanic whites.
More favored explanations are SES, "cultural dislocation", and depression.
The author goes on to describe several studies that have examined the etiology of population differences in Alzheimer's, one of them finding that higher acculturation to American society among Mexican Americans was associated with higher Alzheimer's risk.

Sunday, October 19, 2008

Selection may not be responsible for worldwide variation in circadian clock genes

some suggestive evidence, at most (look here for related post about PER2 gene variation):

Genetic differences in human circadian clock genes among worldwide populations.
Ciarleglio CM, Ryckman KK, Servick SV, Hida A, Robbins S, Wells N, Hicks J, Larson SA, Wiedermann JP, Carver K, Hamilton N, Kidd KK, Kidd JR, Smith JR, Friedlaender J, McMahon DG, Williams SM, Summar ML, Johnson CH.
J Biol Rhythms. 2008 Aug;23(4):330-40.
Abstract: The daily biological clock regulates the timing of sleep and physiological processes that are of fundamental importance to human health, performance, and well-being. Environmental parameters of relevance to biological clocks include (1) daily fluctuations in light intensity and temperature, and (2) seasonal changes in photoperiod (day length) and temperature; these parameters vary dramatically as a function of latitude and locale. In wide-ranging species other than humans, natural selection has genetically optimized adaptiveness along latitudinal clines. Is there evidence for selection of clock gene alleles along latitudinal/photoperiod clines in humans? A number of polymorphisms in the human clock genes Per2, Per3, Clock, and AANAT have been reported as alleles that could be subject to selection. In addition, this investigation discovered several novel polymorphisms in the human Arntl and Arntl2 genes that may have functional impact upon the expression of these clock transcriptional factors. The frequency distribution of these clock gene polymorphisms is reported for diverse populations of African Americans, European Americans, Ghanaians, Han Chinese, and Papua New Guineans (including 5 subpopulations within Papua New Guinea). There are significant differences in the frequency distribution of clock gene alleles among these populations. Population genetic analyses indicate that these differences are likely to arise from genetic drift rather than from natural selection.

Thursday, October 16, 2008

Lipid profiles and African ancestry

Previous research has found that African ancestry is associated with healthier lipid profiles, compared to European ancestry, and that people of African descent in the UK have lower coronary heart disease compared to whites. Since sex also mediates the risk of cardiovascular disease, this study investigates four variants on the Y-chromosome, in "579 men of different ethnic groups (blacks, South Asians, and whites) from UK and in 301 whites in Italy." All Black and South Asian men were first generation immigrants, so that might be why they don't do any kind of adjustment for differing admixture proportions. Given their conclusion:
"In our study, the men of black African origin carrying the A alleles of both TBL1Y and USP9Y had a more favorable lipoprotein profile, characterized by lower levels of serum triglycerides and higher levels of HDL-cholesterol, thus indicating the existence of a “cardio-protective haplotype.” In contrast, in white men, both from the UK and Italy, and in people of South Asian origin, the lipoprotein profiles were not affected by these genotypes."
...they then have a pretty good discussion of the weaknesses and alternative explanations of their findings. They don't really discuss any kind of adaptive or evolutionary explanation for the population differences, other than to mention, regarding which alleles are ancestral, that:
"The data presented here suggest that G allele of TBL1Y and T allele of USP9Y, reported as the wild-type alleles in whites (http://www.ncbi.nlm.nih.gov/SNP) may be derived from the A alleles of both genes, which are the most frequent in black people of African origin."
Genetic Variants of Y Chromosome Are Associated With a Protective Lipid Profile in Black Men
Paola Russo; Alfonso Siani; Michelle A. Miller; Sharada Karanam; Teresa Esposito; Fernando Gianfrancesco; Gianvincenzo Barba; Fabio Lauria; Pasquale Strazzullo;Francesco P. Cappuccio
Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1569.

Abstract Objective— Gender and ethnicity modulate the phenotypic expression of cardiovascular risk factors. In particular, men are at higher risk of developing cardiovascular diseases compared to women, whereas black populations of African origin display reduced mortality from coronary heart disease (CHD) as compared to both whites and South Asians. Because the male-specific region (MSY) of the human Y chromosome is an obvious candidate for gender-related differences in the development of cardiovascular diseases, we aimed to identify genetic variants of MSY influencing cardiovascular risk profile in different ethnic groups. Methods and Results— We genotyped 4 polymorphisms of MSY (HindIII±, rs768983 of TBL1Y, rs3212292 of USP9Y, and rs9341273 of UTY genes) in 579 men of different ethnic groups (blacks, South Asians, and whites) from UK and in 301 whites in Italy. We found that the TBL1YA USP9YA haplotype, present only in blacks in whom it represents the most frequent allelic combinations (AA: n=125; all other combinations: n=45), was associated with lower levels of triglycerides (P=0.025) and higher levels of HDL-cholesterol (P=0.005) as compared to the other haplotypes. Conclusion— The TBL1YA USP9YA haplotype of the Y chromosome, present only in black people of African origin, attributes a favorable lipoprotein pattern, likely to contribute to their reduced susceptibility to coronary heart disease. The study evaluated the association of genetic variants of the male-specific region of the Y chromosome with cardiovascular risk factors in different ethnic groups. The most frequently observed haplotype in black people was associated with a favorable lipoprotein pattern, thus contributing to the lower rate of cardiovascular diseases in blacks.

Wednesday, October 15, 2008

Baldness genetics

Dan at Genetic Future has a great post on a couple of recent genome-wide association studies on male pattern baldness.

Tuesday, October 14, 2008

Genetic determinants of Vitamin D levels among Hispanics and African Americans

This study has a large diverse sample and they look at the association between variants in three vitamin D related genes and vitamin D levels in the blood. They find an association between variants in the DBP (vitamin D Binding Protein gene) and plasma levels of 25(OH)D and 1,25(OH)2D in all three populations. I wonder how these polymorphisms differ in frequency and haplotype structure between groups.

Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans.
Corinne D. Engelman, Tasha E. Fingerlin, Carl D. Langefeld, Pamela J. Hicks, Stephen S. Rich, Lynne E. Wagenknecht, Donald W. Bowden and Jill M. Norris
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 9 3381-3388
Context: Vitamin D deficiency is associated with many adverse health outcomes, yet little is known about the genetic epidemiology of vitamin D or its metabolites. Objective: Our objective was to examine the relationship among three vitamin D-related genes and levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in Hispanics (HAs) and African Americans (AAs). Design and Setting: The cross-sectional Insulin Resistance Atherosclerosis Family Study recruited and examined subjects in: Los Angeles, California (AAs; 513 individuals from 42 families); San Luis Valley (SLV), Colorado (HAs; 513 individuals from 30 families); and San Antonio (SA), Texas (HAs; 504 individuals from 58 families). Main Outcome Measures: Plasma levels of 25(OH)D and 1,25(OH)2D were measured. Results: Levels of 25(OH)D were highest in SLV-HAs [18.3 ± 7.7 ng/ml (45.7 ± 19.2 nmol/liter)], lower in SA-HAs [14.6 ± 6.4 ng/ml (36.4 ± 16.0 nmol/liter)], and lowest in AAs [11.0 ± 5.4 ng/ml (27.5 ± 13.5 nmol/liter)]. Levels of 1,25(OH)2D were similar in AAs [43.5 ± 13.9 pg/ml (113.1 ± 36.1 pmol/liter)] and SLV-HAs [43.2 ± 13.3 pg/ml (112.3 ± 34.6 pmol/liter)], but higher in SA-HAs [48.6 ± 17.0 pg/ml (126.4 ± 44.2 pmol/liter)]. After adjusting for gender and age within the site, two single nucleotide polymorphisms (SNPs) in the vitamin D binding protein gene (DBP), rs4588 and rs7041, were associated with 25(OH)D, and one SNP in the DBP, rs4588, was associated with 1,25(OH)2D at all three study centers. Conclusions: SNPs in the DBP are associated with levels of 25(OH)D and 1,25(OH)2D in HA and AA participants in the Insulin Resistance Atherosclerosis Family Study.

Thursday, October 09, 2008

Why was lactase persistence selected for?

This paper has been discussed by Razib at GNXP, and probably others. I thought I would take a closer look at it myself.
One of the main findings here is the north-south gradient within England in the frequency of the lactase persistence allele.
But they also examine relationships between this genotype and health measures in order to uncover the mechanism by which lactase persistence may have been selected for.
For example, did lactase persistence arise due to the benefits (sugar, protein, fat) or because it enabled one to avoid the ill effects of lactose non-persitence (adverse health reactions)? In this paper, they test for associations between the LCT genotype and various health-related measures.
They also have a good discussion about the selection pressures that may have led to the lactase persistence trait being favored. Among the hypotheses, many of which I had never heard of, as outlined in the paper:

1) "nutritional (and survival) advantage of milk consumption in populations that have milk availability"

2) "the calcium absorption hypothesis which considers the ability to use milk as of particular importance for high latitude
populations with low ultraviolet light exposure who are thus subject to potential vitamin D deficiency and poor calcium absorption and for whom the calcium absorption-stimulating effect of lactose would increase fitness."

3) "a reduced diarrhoeal disease mortality hypothesis that considers that, in populations that have become high consumers of milk, this consumption will increase risk of diarrhoeal disease in individuals who are not lactase persistent and thus select for lactase persistence"

4) specifically for African populations: "in arid regions with animal husbandry practices allowing access to milk, the ability to use milk has a selective advantage through the provision of water and electrolytes"

5) "the enhanced fertility by early weaning hypothesis that postulates that lactase persistence leads to earlier weaning and that earlier cessation of breastfeeding reduces the infertile period following each birth"

It doesn't seem like this study provides any conclusive or even suggestive evidence in favor or against any of these hypotheses, although there is some data that does goes against the diarrhea hypothesis:
"the consequences of prolonged childhood diarrhoeal disease that might be expected in survivors – shorter body height, leg length and perhaps higher blood pressure – were not seen in our data"
Lactase persistence-related genetic variant: population substructure and health outcomes
George Davey Smith, Debbie A Lawlor, Nic J Timpson, Jamil Baban, Matt Kiessling, Ian N M Day and Shah Ebrahim
European Journal of Human Genetics advance online
Abstract: Lactase persistence is an autosomal-dominant trait that is common in European-derived populations. A basic tendency for lactase persistence to increase from the southeast to the northwest across European populations has been noted, but such trends within countries have not been extensively studied. We genotyped the C/T-13910 variant (rs4988235) that constitutes the putatively causal allele for lactase persistence (T allele representing persistence) in a general population sample of 3344 women aged 60–79 years from 23 towns across Britain. We found an overall frequency of 0.253 for the C (lactase non-persistence) allele, but with considerable gradients of decreasing frequency from the south to the north and from the east to the west of Britain for this allele. Daily sunlight was positively related to C (non-persistence) allele prevalence. However, sunlight exposure and latitude are strongly correlated, and it was not possible to identify which is the primary factor statistically underlying the distribution of lactase persistence. The C/T-13910 variant (rs4988235) was not related to drinking milk or bone health (although drinking milk itself was protective of bone health), and was essentially unrelated to a wide range of other lifestyle, health and demographic characteristics. One exception was general health being rated as being poor or fair, for which there was an odds ratio of 1.38 (1.04, 1.84) for women homozygous for the C allele; on adjustment for latitude and longitude of place of birth, this attenuated to 1.19 (0.87, 1.64). The lactase persistence variant could contribute to the examination of data for the existence of, and then statistical control for, population substructure in genetic association studies.

Wednesday, October 08, 2008

Adipose tissue expandability explains onset of metabolic syndrome?

When studying disease traits it is always preferable to understand all elements of the etiological pathway.
A recent paper in PLoS Biology titled "It's Not How Fat You Are, It's What You Do with It That Counts" describes the "Adipose Expandability Hypothesis" as a way of explaining why some individuals develop metabolic syndrome and why others don't, regardless of how obese they are. What matters is your ability to store fat. If you're good at it you can stave off further health complications. If you're not good at it, you start storing fat in organ tissue, leading to further health complications even if you have no excess body fat.

Sunday, October 05, 2008

Predicting hair color from genes

It seems like we're getting closer to understanding the genetic basis of traits like skin, hair and eye pigmentation. Although it is generally assumed that it will be difficult to fully grasp the genetics of complex traits, it could be within reach in the near-term for these types of traits. Understanding the genetic basis of these traits will provide some guiding principles for uncovering the genetic basis of more 'complex' complex traits, as well as about the evolutionary genetic process, population histories, and interactions with environmental factors.
So what do we learn from this paper (see abstract below) on the association between SLC45A2 variants and hair color among Polish subjects?
First, from the intro, with respect to predicting red hair color:
"Nowadays, red hair phenotype is being predicted using
assays that rely on examination of the single MC1R gene, and this allows correct inference in more than 90% of cases (Grimes et al. 2001; Branicki et al. 2007)."
Back to this study, they basically find a rare variant in SLC45A2 that increases a person's odds of having black hair by about seven.

"However, in the present study, 3.6% of red-haired individuals were found to have the L374 allele associated with darker pigmentation. All of them had two MC1R alterations, which are considered as major function mutations strongly affecting receptor performance (data not present). All these individuals had fair skin and blue eyes. This indicates a predominant role of the MC1R gene."
Association of the SLC45A2 gene with physiological human hair colour variation
Wojciech Branicki, Urszula Brudnik, Jolanta Draus-Barini, Tomasz Kupiec and Anna Wojas-Pelc
Journal of Human Genetics Early online
Abstract: Pigmentation is a complex physical trait with multiple genes involved. Several genes have already been associated with natural differences in human pigmentation. The SLC45A2 gene encoding a transporter protein involved in melanin synthesis is considered to be one of the most important genes affecting human pigmentation. Here we present results of an association study conducted on a population of European origin, where the relationship between two non-synonymous polymorphisms in the SLC45A2 gene — rs26722 (E272K) and rs16891982 (L374F) — and different pigmentation traits was examined. The study revealed a significant association between both variable sites and normal variation in hair colour. Only L374F remained significantly associated with hair colour when both SNPs were included in a logistic regression model. No association with other pigmentation traits was detected in this population sample. Our results indicate that the rare allele L374 significantly increases the possibility of having black hair colour (OR = 7.05) and thus may be considered as a future marker for black hair colour prediction.

Wednesday, October 01, 2008

Ancient origin of genes associated with human genetic disease

via Dienekes, an interesting paper on the temporal origin of disease-related genes.

An ancient evolutionary origin of genes associated with human genetic diseases
Tomislav Domazet-Loo and Diethard Tautz
Molecular Biology and Evolution
Abstract: Several thousand genes in the human genome have been linked to a heritable genetic disease. The majority of these appear to be non-essential genes (i.e. are not embryonically lethal when inactivated) and one could therefore speculate that they are late additions in the evolutionary lineage towards humans. Contrary to this expectation, we find that they are in fact significantly over-represented among the genes that have emerged during the early evolution of the metazoa. Using a phylostratigraphic approach, we have studied the evolutionary emergence of such genes at 19 phylogenetic levels. The majority of disease genes was already present in the eukaryotic ancestor and the second largest number has arisen around the time of evolution of multicellularity. Conversely, genes specific to the mammalian lineage are highly underrepresented. Hence, genes involved in genetic diseases are not simply a random subset of all genes in the genome, but are biased towards ancient genes.

Ethnicity, genetic variant at KCNMB1, sex, and asthma

An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity.
Seibold MA, Wang B, Eng C, Kumar G, Beckman KB, Sen S, Choudhry S, Meade K, Lenoir M, Watson HG, Thyne S, Williams LK, Kumar R, Weiss KB, Grammer LC, Avila PC, Schleimer RP, Burchard EG, Brenner R.
Hum Mol Genetics 2008 Sep 1;17(17):2681-90.
Abstract: A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the beta1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure--forced expiratory volume (FEV(1)) % of predicted value. The 818T allele is associated with a clinically significant decline (-13%) in FEV(1) in both cohorts of asthmatics among males but not females (P(combined) = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the beta1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.

Is ethnic self-identification a good predictor of health risks?

Ability of Ethnic Self-Identification to Partition Modifiable Health Risk Among US Residents of Mexican Ancestry.
Barger SD, Gallo LC.
Am J Public Health. 2008 Sep 17
Objectives. We examined the relationship between ethnic self-identification and the partitioning of health risk within a Mexican American population. Methods. We combined data from the 2000 to 2002 National Health Interview Surveys to obtain a large (N=10044) sample of US residents of Mexican ancestry. We evaluated health risk, defined as self-reported current smoking, overweight, and obesity, and compared the predictive strength of health risk correlates across self-identified Mexican and Mexican American participants. Results. Self-identified Mexican participants were less likely to smoke (odds ratio [OR]=0.70; 95% confidence interval[CI] = 0.60, 0.83; P<.001) and to be obese (OR=0.66; 95% CI=0.56, 0.77; P<.001) than were self-identified Mexican American participants. Within-group analyses found that sociodemographic predictors had inconsistent and even contradictory patterns of association with health risk across the 2 subgroups. Health risk was consistently lower among immigrants relative to US-born participants. Ethnic self-identification effects were independent of socioeconomic status. Conclusions. US residents of Mexican ancestry showed substantial within-group differences in health risk and risk correlates. Ethnic self-identification is a promising strategy to clarify differential risk and may help resolve apparent discrepancies in health risk correlates in this literature.

Thursday, September 25, 2008

Protective factor against breast cancer in Black women?

Breast cancer incidence has been found to be higher in those with higher SES, and incidence is highest among Whites, followed by Blacks, then Asians and Hispanics. Using several previous studies, this study finds that the disparity in breast cancer risk between ethnic groups can be accounted for by differences in SES, except for the disparity between Blacks and others.
"In contrast, for the black population, seven of the eight
analyzed datasets showed no difference in the incidence
of breast cancer at highest level of SES compared to the
lowest level, with only one dataset demonstrating a statistically significant disparity (data set 1: IRR 1.39, lower limit of 95% CI=1.04). This suggests that, as opposed to the apparent contributory effect of high SES on breast cancer risk in white, Hispanic and Asian/Pacific-Islander women, the risk of breast cancer in black women may not be significantly modified by SES."
in the conclusion:
"As for black women, the overall lack of statistically significant incidence rate ratios in Table 1 suggests that SES effects do not play an important role in modifying the risk of breast cancer in this population. This suggestion is supported by Chlebowski’s analysis, in which adjustment for SES-correlated breast cancer risk factors failed to eliminate the differencein hazard ratio of between black women and women of other races. Taken together, these findings imply the presence of a protective factor, which is not modified by SES, against breast cancer in black women."
There's a brief mention at the end about the grade and aggressiveness of breast cancer among Black women.

Disparities in breast cancer incidence across racial/ethnic strata and socioeconomic status: a systematic review
Vainshtein J.
J Natl Med Assoc. 2008 Jul;100(7):833-9.
OBJECTIVES: A higher incidence of breast cancer has been reported both in white women and women of higher socioeconomic status (SES) compared to women of other races and lower SES, respectively. We explored whether differences in SES can account for disparities in breast cancer incidence between races. METHODS: We identified several studies published between 1990 and 2007 that addressed disparities in breast cancer incidence across racial and socioeconomic strata. For each study, we calculated incidence rate ratios (IRRs) for breast cancer incidence in the highest strata to lowest strata of SES for white, black, Hispanic and Asian/Pacific-Islander populations. We then used these IRRs to compare trends in SES and breast cancer incidence between races and across studies. RESULTS: The studies we identified revealed that the magnitude of the disparity in breast cancer incidence between races decreases with increasing SES. While individual census-tract based studies' methods of assessing the association between SES and breast cancer incidence did not identify consistent trends between races, adjustment for risk factors closely correlated with SES eliminated the statistical differences in breast cancer incidence between women of white, Hispanic and Asian/Pacific-Islander, but not black, ethnicity. CONCLUSION: We found that racial differences in breast cancer incidence can largely be accounted for by ethnic differences in SES among white, Hispanic and Asian/Pacific-Islander women, but not between these populations and black women. We further highlight important differences in methodology between previously published studies that may account for their disparate findings.

Wednesday, September 24, 2008

Four Stone Hearth Anthropology Blog Carnival

I'm happy to be hosting the 50th edition of the Four Stone Hearth Anthropology Blog Carnival!
We've got a wide array of Anthropology topics. I'll go from social/cultural anthropology, then into archaeology, and then into biological anthropology.

Daniel at Neuroanthropology shares with us Alesha Sivartha's collection of drawings representing the domains of life and culture that brains might be devoted to dealing with. This is interesting in the sense that evolutionary psychologists have argued that the brain is not like a general purpose computer, but rather like a Swiss army knife with domain specific mechanisms evolved to deal with specific problems such as face recognition, social relationships, mental maps, etc..

Daniel has another interesting post about Race in the Race for President of the US, which reminds us that racial dynamics are never far from the lived experience of Americans.

Magnus Reuterdahl at Testimony at the Spade discusses Mark Twain's visit to Jonkoping, Sweden.

Terry Toohill, guest blogger at Remote Central, discusses the evidence and misconceptions surrounding the processes of evolution, and might I add, provides plenty of references.

Martin at Aardvarchaeology shares his experience with the trials and tribulations of archaeological digs in Sweden.

At the Southeast Asian Archaeology Newblog, we see that six new Neolithic burials from Sarawak from the Niah cave complex have been recently put on display.
"More significantly, the skeletons are of the Australomelanasoid affinity, which means they were natives of Sundaland (the geological land shelf on which much of island Southeast Asia sits on) and possibly represent the continuous habitation of the cave site rather part of the migratory group originating from Southern China that is thought to populate Southeast Asia in this period" (from 2-3 thousand years ago)
The past couple of weeks has seen several stories about Neanderthals.
As usual, John Hawks has a wealth of information and insight:
Still on the Neanderthal topic, Julien at A Very Remote Period Indeed reviews the new National Geographic series on Neanderthals. He focuses on the evidence for whether there were hostile or peaceful relations between modern Humans and Neanderthals, on the relative (and complementary) merit of fossil, archaeological and genetic data in interpreting what happened in the past. He closes with a discussion about the reconstruction of a face of a Neanderthal female, discussed on other blogs as well.

Afarensis also discusses a paper about Neanderthal brain size and maturation which argues that Neanderthals grew quickly but matured later than modern humans, suggesting that their overall life history was perhaps slower paced than that of modern humans. Afarensis also discusses the use of marine food resources by Neanderthals, before the most recent piece of evidence came out in PNAS.

Dienekes has his usual dizzying array of posts from a wide variety of topics in evolutionary and molecular anthropology.
I'll just point out the post on Stonehenge and how it has been dated more accurately, and how it has been suggested that it was a healing center.

Razib at GNXP has a great post on a recent NYT article about David Goldstein on the HapMap, selection and race. Many other bloggers (John Hawks, Genetic Future etc...) have also commented on this article. In this article David Goldstein questions the efficiency of the process by which we currently look for the genetic basis for disease (and intelligence).

Finally, let me point you to Kambiz's always excellent and thorough Anthropology.net blog. He has recently posted about a new study published in PLoS Genetics that examines how genes involved in the immune system can predict human mating patterns.
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