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.

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.

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.

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.

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.

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."

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.

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.

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.

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.