Polynesian chickens in the pre-Columbian Americas...maybe not, after all

see here for the post about this from last year.

Indo-European and Asian origins for Chilean and Pacific chickens revealed by mtDNA
Jaime Gongora, Nicolas J. Rawlence, Victor A. Mobegi§, Han Jianlin, Jose A. Alcalde, Jose T. Matus, Olivier Hanotte, Chris Moran, Jeremy J. Austin, Sean Ulm, Atholl J. Anderson, Greger Larson, and Alan Cooper
PNAS

Abstract: European chickens were introduced into the American continents by the Spanish after their arrival in the 15th century. However, there is ongoing debate as to the presence of pre-Columbian chickens among Amerindians in South America, particularly in relation to Chilean breeds such as the Araucana and Passion Fowl. To understand the origin of these populations, we have generated partial mitochondrial DNA control region sequences from 41 native Chilean specimens and compared them with a previously generated database of ≈1,000 domestic chicken sequences from across the world as well as published Chilean and Polynesian ancient DNA sequences. The modern Chilean sequences cluster closely with haplotypes predominantly distributed among European, Indian subcontinental, and Southeast Asian chickens, consistent with a European genetic origin. A published, apparently pre-Columbian, Chilean specimen and six pre-European Polynesian specimens also cluster with the same European/Indian subcontinental/Southeast Asian sequences, providing no support for a Polynesian introduction of chickens to South America. In contrast, sequences from two archaeological sites on Easter Island group with an uncommon haplogroup from Indonesia, Japan, and China and may represent a genetic signature of an early Polynesian dispersal. Modeling of the potential marine carbon contribution to the Chilean archaeological specimen casts further doubt on claims for pre-Columbian chickens, and definitive proof will require further analyses of ancient DNA sequences and radiocarbon and stable isotope data from archaeological excavations within both Chile and Polynesia.

Diabetes and African admixture

several interesting things in this paper:
- comparison of three admixture estimation methods and using various number of markers
- looking at the effect of admixture on association between diabetes and variants in diabetes candidate genes.

Probably the most important finding is the high proportion of African ancestry in females with diabetes, compared to female controls, male cases and controls.
Their interpretation:

If AA females with T2DM have genes of “African descent” that are involved in energy storage and expenditure, but also influence or are influenced by gender-specific pathways, when exposed to a westernized lifestyle, these individuals will be at an increased risk of obesity and subsequently developing T2DM.

also, their finding makes sense in terms of:

the unexplained increase in risk for having a family history of ESRD that is present among African American women, relative to men (Freedman et al. 2005; McClellan et al. 2007)

Exploration of the utility of ancestry informative markers for genetic association studies of African Americans with type 2 diabetes and end stage renal disease.
Keene KL, Mychaleckyj JC, Leak TS, Smith SG, Perlegas PS, Divers J, Langefeld CD, Freedman BI, Bowden DW, Sale MM.
Hum Genetics Online First 2008 Jul 25.

Abstract: Admixture and population stratification are major concerns in genetic association studies. We wished to evaluate the impact of admixture using empirically derived data from genetic association studies of African Americans (AA) with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Seventy ancestry informative markers (AIMs) were genotyped in 577 AA with T2DM-ESRD, 596 AA controls, 44 Yoruba Nigerian (YRI) and 39 European American (EA) controls. Genotypic data and association results for eight T2DM candidate gene studies in our AA population were included. Ancestral estimates were calculated using FRAPPE, ADMIXMAP and STRUCTURE for all AA samples, using varying numbers of AIMs (25, 50, and 70). Ancestry estimates varied significantly across all three programs with the highest estimates obtained using STRUCTURE, followed by ADMIXMAP; while FRAPPE estimates were the lowest. FRAPPE estimates were similar using varying numbers of AIMs, while STRUCTURE estimates using 25 AIMs differed from estimates using 50 and 70 AIMs. Female T2DM-ESRD cases showed higher mean African proportions as compared to female controls, male cases, and male controls. Age showed a weak but significant correlation with individual ancestral estimates in AA cases (r (2) = 0.101; P = 0.019) and in the combined set (r (2) = 0.131; P = 3.57 x 10(-5)). The absolute difference between frequencies in parental populations, absolute delta, was correlated with admixture impact for dominant, additive, and recessive genotypic models of association. This study presents exploratory analyses of the impact of admixture on studies of AA with T2DM-ESRD and supports the use of ancestral proportions as a means of reducing confounding effects due to admixture.

What do people do with health information from their DNA?

This project partly aims to determine how people respond to personal genomic information about their health risks.
Here's an NIH news story about the study.
The money line from the abstract: "We recommend that a considerable research commitment be made now in order to successfully bridge the rapidly widening gap between gene-disease association research and the critical (but slower and more involved) investigations into public health and clinical utility."

Putting science over supposition in the arena of personalized genomics
Colleen M McBride, Sharon Hensley Alford, Robert J Reid, Eric B Larson, Andreas D Baxevanis & Lawrence C Brody
Nature Genetics 40, 939 - 942 (2008)

Abstract: We explore the process of going from genome discovery to evaluation of medical impact and discuss emerging challenges faced by the scientific community. The need to confront these challenges is heightened in a climate where unregulated genetic tests are being marketed directly to the general public1, 2. Specifically, we characterize the delicate balance involved in deciding when genomic discoveries such as gene-disease associations are 'ready' to be evaluated as potential tools to improve health. We recommend that a considerable research commitment be made now in order to successfully bridge the rapidly widening gap between gene-disease association research and the critical (but slower and more involved) investigations into public health and clinical utility. Lastly, we describe a large, ongoing, early-phase research project, the Multiplex Initiative, which is examining issues related to the utility of genetic susceptibility testing for common health conditions.

Mess up CCR2 using zinc finger nucleases and prevent HIV?

this is pretty cool...using zinc finger nucleases to mimic the protective effect of the CCR5delta32 mutation against HIV infection.
The fourth author has a hell of a first name!

Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases
Elena E Perez, Jianbin Wang, Jeffrey C Miller, Yann Jouvenot, Kenneth A Kim, Olga Liu1, Nathaniel Wang, Gary Lee, Victor V Bartsevich, Ya-Li Lee, Dmitry Y Guschin, Igor Rupniewski, Adam J Waite, Carmine Carpenito, Richard G Carroll, Jordan S Orange, Fyodor D Urnov, Edward J Rebar, Dale Ando, Philip D Gregory, James L Riley, Michael C Holmes & Carl H June
Nature Biotechnology 26, 808 - 816 (2008)

Abstract: Homozygosity for the naturally occurring 32 deletion in the HIV co-receptor CCR5 confers resistance to HIV-1 infection. We generated an HIV-resistant genotype de novo using engineered zinc-finger nucleases (ZFNs) to disrupt endogenous CCR5. Transient expression of CCR5 ZFNs permanently and specifically disrupted 50% of CCR5 alleles in a pool of primary human CD4+ T cells. Genetic disruption of CCR5 provided robust, stable and heritable protection against HIV-1 infection in vitro and in vivo in a NOG model of HIV infection. HIV-1-infected mice engrafted with ZFN-modified CD4+ T cells had lower viral loads and higher CD4+ T-cell counts than mice engrafted with wild-type CD4+ T cells, consistent with the potential to reconstitute immune function in individuals with HIV/AIDS by maintenance of an HIV-resistant CD4+ T-cell population. Thus adoptive transfer of ex vivo expanded CCR5 ZFN–modified autologous CD4+ T cells in HIV patients is an attractive approach for the treatment of HIV-1 infection.

Recent selection among non-Africans at gene related to circadian rhythms

The gene PER2 is involved in the regulation of the circadian clock.
What are the patterns of variation in this gene across worldwide human populations?
They examine this question by sequencing 20 people, then genotyping 499 people from around the world at five polymorphic sites. They then looked at haplotype diversity, linkage disequilibrium, Fst and other measures of diversity.
They look for a correlation between latitude and measures of genetic distance, and examine differences in genetic diversity between groups with similar latitude...and overall, find no evidence of a relationship between genetic variation at this locus and latitute.
They do find high levels of differentiation between populations and they find a low degree of sequence variation in the associated haplotypes, suggesting recent selection. For the haplogroup with the lowest sequence diversity they fnd a TMRCA of 8.7 +- 8.7 kya.
There's some discussion at the end regarding variation in this gene being associated with a person's preference for morningtime or eveningtime... they didn't look at these specific variants. It remains to be seen what explains the patterns of variation and recent selection that they find.

Genetic diversity patterns at the human clock gene period 2 are suggestive of population-specific positive selection
Fulvio Cruciani, Beniamino Trombetta, Damian Labuda, David Modiano, Antonio Torroni, Rodolfo Costa and Rosaria Scozzari
European Journal of Human Genetics Advance online pub. 25 June 2008

Abstract: Period 2 (PER2) is a key component of the mammalian circadian clock machinery. In humans, genetic variation of clock genes or chronic disturbance of circadian rhythmicity has been implied in the onset of several phenotypes, ranging from periodic insomnias to advanced or delayed sleep phases, to more severe disorders. Peculiar geographic diversity patterns in circadian genes might represent an adaptive response to different light/dark cycles or environmental changes to which different human populations are exposed. To investigate the degree and nature of PER2 gene variation in human populations of different geographic origin, and its possible correlation with different latitudes, we sequenced a 7.7 kb portion of the gene in 20 individuals worldwide. In total, 25 variable sites were identified. The geographic distribution of haplotypes defined by five polymorphic sites was analyzed in 499 individuals from 11 populations from four continents. No evidence for latitude-driven selective effects on PER2 genetic variability was found. However, a high and significant difference in the geographic distribution of PER2 polymorphisms was observed between Africans and non-Africans, suggesting a history of geographically restricted natural selection at this locus. In support of this notion, we found several signals for selection in the sequences. The putative selected haplotype showed a recent coalescent age (8.7 Kyr), and an unusually high frequency in non-African populations. Overall, these findings indicate that a human clock-relevant gene, PER2, might have been influenced by positive selection, and offer preliminary insights into the evolution of this functional class of genes.

Ten commandments of race and genetics research

When I saw this New Scientist article a few days ago, I found it a bit too PC and irksome, so didn't think it was worth blogging about, but thankfully Dienekes makes some good comments on each of the ten points.
I'll just add that I think that the use of the word "race" is getting really old and counterproductive, partly because it's often used as a straw man.

Another tradeoff in order to avoid malaria?

Genetic trait boosts AIDS risks in Blacks in Yahoo! News. Unfortunately, I don't have access to the full text of this paper. It looks really good, uses access to a large sample, and shows biological effects of genetic variants.
I assume and hope that they control for population stratification when they find that the "DARC −46C/C is associated with 40% increase in the odds of acquiring HIV-1"

Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility
Weijing He, Stuart Neil, Hemant Kulkarni, Edward Wright, Brian K. Agan, Vincent C. Marconi, Matthew J. Dolan, Robin A. Weiss, and Sunil K. Ahuja
Cell Host and Microbe Volume 4, Issue 1, 17 July 2008, Pages 52-62

Abstract: Duffy antigen receptor for chemokines (DARC) expressed on red blood cells (RBCs) influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the RBC receptor for Plasmodium vivax. Africans with DARC −46C/C genotype, which confers a DARC-negative phenotype, are resistant to vivax malaria. Here, we show that HIV-1 attaches to RBCs via DARC, effecting trans-infection of target cells. In African Americans, DARC −46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, 11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative RBC status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV/AIDS susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation.

E.O. Wilson profile

...in the New York Times, about ant species (14,001 of them!!!), recent paper on group selection, Dawkins' response in New Scientist (which I can't seem to locate), and sociobiology.
see also John Hawks and Razib.

Doggie ancestry

I heard about this, but never saw the details:

From the website of Doggie DNAPrint:

For example, in 2004 Parker et al. sequenced 75 SNP and 96 microsatellite loci in 85 dog breeds and showed that modern dog breeds are distinct genetic units and that breed can be accurately determined from dog DNA. Looking back relatively far in the dog family tree, Parker et al. noted that there appear to be 4 main dog breed types:

1. The wolf-like (yellow in the K=4 part of Figure 1)
2. The Herders (green in the K=4 part of Figure 1)
3. The Hunters (red in the K=4 part of Figure 1), and
4. The Mastiff (blue in the K=4 part of Figure 1)

Figure 1 (above) shows some of their data (Figure 3 of Parker et al., 2004), where dog breeds are clustered based on their affinity with the founders or parental dog populations for each of these 3 ancestral groups. Dog breeds such as the Akita, Chow Chow and Siberian Husky fall into the Wolf-Like group, Collies, Greyhounds, Borzoi etc. fall into the Herder group, Beagles, Pointers and Terriers (etc.) fall into the Hunter group and Bulldogs, Mastiffs, Boxers (etc.) fall into the Mastiff group.You will note that, due to the history of their origins, each breed is characterized by a unique ratio of admixture among these families.

The problems with genome-wide association scans

Dan at Genetic Future has a great post from a few months ago that I finally read in its entirety:
Why do genome-wide scans fail?
It looks at the present limitations and future promises of this technique.

NIH Intramural Center for Genomics and Health Disparities

There's an interview in Nature Medicine with the director, Charles Rotimi, of this newly established NIH center.

We collect demographic and migrational information from our study participants, including Africans and African-Americans. This information enables us to develop models to test how 'old' genes from Africa work in new environments such as the United States to increase our risk for diseases or to protect us from getting certain diseases. We also collect information on diet and data relating to education and income. But I would say that most of the very critical factors in term of health disparity are things to do with social structure, the communities where people live, and social factors such as racism. These are extremely difficult factors for a setup like ours to fully capture. But there are other groups we intend to collaborate with who can help address such questions.

He cautions against using racial labels in medicine and medical research, and briefly discusses the BiDIL controversy.

Structure-informative SNPs among European Americans

100- 200 carefully selected SNPs are enough, they say, to adequately control for structure among European Americans "while maintaining power in association studies". Their method makes no assumptions about the origin or ancestry of individuals, nor, unfortunately, do they even have any information on this.
Also, they find very little overlap between the AIMs (ancestry informative markers- actually, structure informative markers) they propose here and those found in the several other previous studies looking at genetic diversity in Europe, but:

The greatest overlap is found between the panel we propose here and the 1,441 SNPs proposed by Tian et al. [27] as distinguishing between northern European and Ashkenazi Jewish ancestry.

I'm sure Dienekes will have a field day with this one.

Tracing Sub-Structure in the European American Population with PCA-Informative Markers
Peristera Paschou, Petros Drineas, Jamey Lewis, Caroline M. Nievergelt, Deborah A. Nickerson, Joshua D. Smith, Paul M. Ridker, Daniel I. Chasman, Ronald M. Krauss, Elad Ziv
PLoS Genetics 4(7)

Abstract: Genetic structure in the European American population reflects waves of migration and recent gene flow among different populations. This complex structure can introduce bias in genetic association studies. Using Principal Components Analysis (PCA), we analyze the structure of two independent European American datasets (1,521 individuals–307,315 autosomal SNPs). Individual variation lies across a continuum with some individuals showing high degrees of admixture with non-European populations, as demonstrated through joint analysis with HapMap data. The CEPH Europeans only represent a small fraction of the variation encountered in the larger European American datasets we studied. We interpret the first eigenvector of this data as correlated with ancestry, and we apply an algorithm that we have previously described to select PCA-informative markers (PCAIMs) that can reproduce this structure. Importantly, we develop a novel method that can remove redundancy from the selected SNP panels and show that we can effectively remove correlated markers, thus increasing genotyping savings. Only 150–200 PCAIMs suffice to accurately predict fine structure in European American datasets, as identified by PCA. Simulating association studies, we couple our method with a PCA-based stratification correction tool and demonstrate that a small number of PCAIMs can efficiently remove false correlations with almost no loss in power. The structure informative SNPs that we propose are an important resource for genetic association studies of European Americans. Furthermore, our redundancy removal algorithm can be applied on sets of ancestry informative markers selected with any method in order to select the most uncorrelated SNPs, and significantly decreases genotyping costs.

Metabolomics

There's an interesting article in the Economist about ways to diagnose what the body is undergoing. For example:

Douglas Kell, a researcher at the University of Manchester in Britain, has already created a computer model based on metabolite profiles in blood plasma that can single out pregnant women who are developing pre-eclampsia, or dangerously high blood pressure. Research published last year by Rima Kaddurah-Daouk, a psychiatrist at the Duke University Medical Centre in America, may not only provide a test for schizophrenia, but also help with its treatment. She found a pattern of metabolites present only in the blood of people who had been diagnosed with schizophrenia. The patterns change according to the antipsychotic drugs patients take and this may throw light on why some respond well to certain drugs, but others suffer severe side-effects.

Eventually we could go back and forth between metabolomics and genomics (and microbiomics) in understanding various metabolic pathways.

The genetics of metabolic syndrome across populations

Regions of strong genetic association with phenotypes related to metabolic syndrome are found to differ between groups (whites, Mexican Americans, African Americans, and Japanese Americans).

Genome-wide Linkage Scan for the Metabolic Syndrome: The GENNID Study
Karen L. Edwards, Carolyn M. Hutter, Jia Yin Wan, Helen Kim and Stephanie A. Monks
Obesity (2008) 16 7, 1596–1601

Abstract: In the United States, the metabolic syndrome (MetS) constitutes a major public health problem with over 47 million persons meeting clinical criteria for MetS. Numerous studies have suggested genetic susceptibility to MetS. The goals of this study were (i) to identify susceptibility loci for MetS in well-characterized families with type 2 diabetes (T2D) in four ethnic groups and (ii) to determine whether evidence for linkage varies across the four groups. The GENNID study (Genetics of NIDDM) is a multicenter study established by the American Diabetes Association in 1993 and comprises a comprehensive, well-characterized resource of T2D families from four ethnic groups (whites, Mexican Americans, African Americans, and Japanese Americans). Principal component factor analysis (PCFA) was used to define quantitative phenotypes of the MetS. Variance components linkage analysis was conducted using microsatellite markers from a 10-cM genome-wide linkage scan, separately in each of the four ethnic groups. Three quantitative MetS factors were identified by PCFA and used as phenotypes for MetS: (i) a weight/waist factor, (ii) a blood pressure factor, and (iii) a lipid factor. Evidence for linkage to each of these factors was observed. For each ethnic group, our results suggest that several regions harbor susceptibility genes for the MetS. The strongest evidence for linkage for MetS phenotypes was observed on chromosome 2 (2q12.1–2q13) in the white sample and on chromosome 3 (3q26.1–3q29) in the Mexican-American sample. In conclusion, the results suggest that several regions harbor MetS susceptibility genes and that heterogeneity may exist across groups.