Saturday, August 30, 2008

Long term cultural selection for male dominance traits?

Male dominance rarely skews the frequency distribution of Y chromosome haplotypes in human populations
J. Stephen Lansing, Joseph C. Watkins, Brian Hallmark, Murray P. Cox, Tatiana M. Karafet, Herawati Sudoyo, and Michael F. Hammer
PNAS August 19, 2008 vol. 105 no. 33 11645-11650
Abstract: A central tenet of evolutionary social science holds that behaviors, such as those associated with social dominance, produce fitness effects that are subject to cultural selection. However, evidence for such selection is inconclusive because it is based on short-term statistical associations between behavior and fertility. Here, we show that the evolutionary effects of dominance at the population level can be detected using noncoding regions of DNA. Highly variable polymorphisms on the nonrecombining portion of the Y chromosome can be used to trace lines of descent from a common male ancestor. Thus, it is possible to test for the persistence of differential fertility among patrilines. We examine haplotype distributions defined by 12 short tandem repeats in a sample of 1269 men from 41 Indonesian communities and test for departures from neutral mutation-drift equilibrium based on the Ewens sampling formula. Our tests reject the neutral model in only 5 communities. Analysis and simulations show that we have sufficient power to detect such departures under varying demographic conditions, including founder effects, bottlenecks, and migration, and at varying levels of social dominance. We conclude that patrilines seldom are dominant for more than a few generations, and thus traits or behaviors that are strictly paternally inherited are unlikely to be under strong cultural selection.

Thursday, August 28, 2008

Why look at genetic association one locus at a time when you can do several loci at a time?

This looks pretty cool. They propose a method of doing association studies by considering several SNPs at once instead of one SNP at a time. Even though this makes biological sense, it seems like the analysis would get messy and cumbersome. They seem to address these issues and analyze their method on previous data sets. They use a "Bayesian inspired" method called: stochastic search maximisation algorithm.
I'll need to read this paper more closely to see exactly how this method compares to previous single-SNP analyses, one of which, they describe in the paper, is on T2D.

Simultaneous Analysis of All SNPs in Genome-Wide and Re-Sequencing Association Studies
Clive J. Hoggart, John C. Whittaker, Maria De Iorio, David J. Balding
PLoS Genetics 4(7)
Abstract: Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible, thanks to developments in stochastic search methods. We used a Bayesian-inspired penalised maximum likelihood approach in which every SNP can be considered for additive, dominant, and recessive contributions to disease risk. Posterior mode estimates were obtained for regression coefficients that were each assigned a prior with a sharp mode at zero. A non-zero coefficient estimate was interpreted as corresponding to a significant SNP. We investigated two prior distributions and show that the normal-exponential-gamma prior leads to improved SNP selection in comparison with single-SNP tests. We also derived an explicit approximation for type-I error that avoids the need to use permutation procedures. As well as genome-wide analyses, our method is well-suited to fine mapping with very dense SNP sets obtained from re-sequencing and/or imputation. It can accommodate quantitative as well as case-control phenotypes, covariate adjustment, and can be extended to search for interactions. Here, we demonstrate the power and empirical type-I error of our approach using simulated case-control data sets of up to 500 K SNPs, a real genome-wide data set of 300 K SNPs, and a sequence-based dataset, each of which can be analysed in a few hours on a desktop workstation.

Wednesday, August 27, 2008

Cultured melanocytes, genotypes and gene expression of skin color genes

Analysis of Cultured Human Melanocytes Based on Polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P Loci
Anthony L Cook, Wei Chen, Amy E Thurber, Darren J Smit, Aaron G Smith, Timothy G Bladen, Darren L Brown, David L Duffy, Lorenza Pastorino, Giovanna Bianchi-Scarra, J Helen Leonard, Jennifer L Stow and Richard A Sturm
Journal of Investigative Dermatology advance online publication 24 July 2008;
Abstract: Single nucleotide polymorphisms (SNPs) within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P genes have been associated with natural variation of pigmentation traits in human populations. Here, we describe the characterization of human primary melanocytic cells genotyped for polymorphisms within the MATP, NCKX5, or OCA2 loci. On the basis of genotype, these cultured cells reflect the phenotypes observed by others in terms of both melanin content and tyrosinase (TYR) activity when comparing skin designated as either "White" or "Black". We found a statistically significant association of MATP-374L (darker skin) with higher TYR protein abundance that was not observed for any NCKX5-111 or OCA2 rs12913832 allele. MATP-374L/L homozygous strains displayed significantly lower MATP transcript levels compared to MATP-374F/F homozygous cells, but this did not reach statistical significance based on NCKX5 or OCA2 genotype. Similarly, we observed significantly increased levels of OCA2 mRNA in rs12913832-T (brown eye) homozygotes compared to rs12913832-C (blue eye) homozygous strains, which was not observed for MATP or NCKX5 gene transcripts. In genotype–phenotype associations performed on a collection of 226 southern European individuals using these same SNPs, we were able to show strong correlations in MATP-L374F, OCA2, and melanocortin-1 receptor with skin, eye, and hair color variation, respectively.

Monday, August 25, 2008

Genetics of T2D among Ashkenazi Jews: Replication and predictive value of genetic information

Last year 10 loci associated with type-2 Diabetes (T2D) were identified in a WGAS (whole genome association study) and replicated in various large samples (Scott et al. 2007). Here, they assess the association between these 10 loci and T2D among Ashkenazi Jews in Israel (all four grandparents are Ashkenazi Jews). They find that most markers show similar ORs as the Scott et al. meta-analysis, and p-values lower than 0.1 for 7 out of the 10 loci. They then look at the predictive power of information on these 10 loci on the risk of developing T2D, and find that it is rather limited (at least among Ashkenazi Jews):
"Consistent with the previous findings showing that such set of SNPs may explain only a small fraction (2–3%) ofthe trait variation (Saxena et al. 2007), we have also found that the predictive value of these findings is relatively limited.
For most individuals, the genotypic information will only modestly alter their baseline risk to develop T2D. Only for a small fraction of the population (about 3%), the genetic information may indicate a decrease or increase of the baseline risk by twofold (upwards or downwards). Consequently, at present, the use of genetic information by clinicians for the identification of patients at risk to develop T2D does not seem too relevant. Nevertheless, it is important to emphasize that the value of gene discovery lies primarily in the understanding of the disease as a means to develop efficient therapies."
Type 2 diabetes susceptibility loci in the Ashkenazi Jewish population.
Bronstein M, Pisanté A, Yakir B, Darvasi A.
Human Genetics
2008 Aug;124(1):101-4.
Abstract: Until last year, type 2 diabetes (T2D) susceptibility loci have hardly been identified, despite great effort. Recently, however, several whole-genome association (WGA) studies jointly uncovered 10 robustly replicated loci. Here, we examine these loci in the Ashkenazi Jewish (AJ) population in a sample of 1,131 cases versus 1,147 controls. Genetic predisposition to T2D in the AJ population was found similar to that established in the previous studies. One SNP, rs7754840 in the CDKAL1 gene, presented a significantly stronger effect in the AJ population as compared to the general Caucasian population. This may possibly be due to the increased homogeneity of the AJ population. The use of the SNPs considered in this study, to identify individuals at high (or low) risk to develop T2D, was found of limited value. Our study, however, strongly supports the robustness of WGA studies for the identification of genes affecting complex traits in general and T2D in particular.

Friday, August 22, 2008

Olfactory receptor genetics in humans and chimpanzees

Several studies of genetic signatures of selection in humans have found something going on with olfactory receptor genes, which has been difficult to interpret. Why would there be strong selection for smelling related traits in the lineage leading to humans (smelling rotting meat, tracking animals??).
In this paper, the authors look at OR (olfactory receptor) genes in humans, chimps and macaques, and finds that:
The pseudogenization rates and the numbers of genes affected by positive selection are also similar between humans and chimpanzees.
...approximately 25% of their functional gene repertoires are species specific due to massive gene losses. These findings suggest that the tempo of evolution of OR [olfactory receptor] genes is similar between humans and chimpanzees, but the OR gene repertoires are quite different between them.
Similar Numbers but Different Repertoires of Olfactory Receptor Genes in Humans and Chimpanzees
Yasuhiro Go, and Yoshihito Niimura
Molecular Biology and Evolution 2008 25(9):1897-1907
Abstract: Animals recognize their external world through the detection of tens of thousands of chemical odorants. Olfactory receptor (OR) genes encode proteins for detecting odorant molecules and form the largest multigene family in mammals. It is known that humans have fewer OR genes and a higher fraction of OR pseudogenes than mice or dogs. To investigate whether these features are human specific or common to all higher primates, we identified nearly complete sets of OR genes from the chimpanzee and macaque genomes and compared them with the human OR genes. In contrast to previous studies, here we show that the number of OR genes (810) and the fraction of pseudogenes (51%) in chimpanzees are very similar to those in humans, though macaques have considerably fewer OR genes. The pseudogenization rates and the numbers of genes affected by positive selection are also similar between humans and chimpanzees. Moreover, the most recent common ancestor between humans and chimpanzees had a larger number of functional OR genes (>500) and a lower fraction of pseudogenes (41%) than its descendents, suggesting that the OR gene repertoires are in a phase of deterioration in both lineages. Interestingly, despite the close evolutionary relationship between the 2 species, approximately 25% of their functional gene repertoires are species specific due to massive gene losses. These findings suggest that the tempo of evolution of OR genes is similar between humans and chimpanzees, but the OR gene repertoires are quite different between them. This difference might be responsible for the species-specific ability of odor perception.

Thursday, August 21, 2008

BRCA1 mutation among Yorubans

They seem to have found the second of 2 known BRCA1 founder mutations in individuals of African descent. Four out of 365 breast cancer patients have this BRCA1 Y101X mutation. Although BRCA1 mutations probably account for a small proportion of breast cancer cases, these mutations are highly penetrant and therefore strong predictors of breast cancer. They discuss how the identification of these population-specific mutations can be used for genetic screening strategies for breast cancer.

Evidence for an ancient BRCA1 mutation in breast cancer patients of yoruban ancestry.
Zhang B, Fackenthal JD, Niu Q, Huo D, Sveen WE, Demarco T, Adebamowo CA, Ogundiran T, Olopade OI
Familial Cancer
Abstract: Background BRCA1 recurrent mutations have rarely been assessed in non-founder populations. Still, identifying such mutations could be important for designing genetic testing strategies for high-risk breast/ovarian cancer families in non-founder populations. Objective To determine whether the recurrent BRCA1 Y101X mutation identified in Yoruban breast cancer patients represents a single historical mutation event, and determine the prevalence of this mutation in a hospital based cohort. Methods 365 breast cancer patients and 177 controls of Yoruban ancestry from Nigeria, unselected for age of onset or family history were screened for the BRCA1 Y101X mutation. The haplotypes on which the Y101X mutation occurred were characterized using microsatellite markers and single-nucleotide polymorphisms (SNPs). Phase ambiguity was resolved using allele-specific PCR. Results The BRCA1 Y101X mutation was detected in four Yoruban patients with no documented family history of breast cancer among a cohort of 365 (1.1, 95% C.I. = 0.43-2.78%) unrelated Yoruban breast cancer patients. This study reveals the four Y101X mutations occur on a single, rare haplotype. Further characterization in a patient of European ancestry with a strong family history of breast/ovarian cancer revealed the same Y101X mutation on the same haplotype as those in the Yoruban carriers. These observations suggest the Y101X mutations identified in the Yoruban patients may have originated from a single mutation event. Conclusions BRCA1 Y101X is the first reported recurrent mutation occurring in patients of African ancestry for which prevalence has been determined. Identification of this mutation in a woman of European ancestry with strong family history of breast/ovarian suggests further that this mutation occurred once, probably many generations ago.

Monday, August 11, 2008

Local recent selection in humans

In this paper the authors use a combined Fst and haplotype block length approach to finding genes/areas that have been under strong recent selection in different populations: about 24 individuals each, of African American, European American, and Han Chinese descent, with 1.6 milion SNPs typed in each.
After identifying haplotype blocks, they compared the average Fst for all SNPs in each block between populations.
Genes involved in skin pigmentation for which they find evidence of positive selection:RAB27A, DCT, EGFR, ATRN, MATP.
They also find that many of the areas under selection are in non-genic locations. They mention the example of the lactase gene is an example of the functional variant being in a regulatory region -- see this recent, interesting article in Science regarding the issue of the importance of genic vs. nongenic variation in evolutionary change (which this picture refers to).
Another interesting finding which they discuss is the small amount of overlap between loci that they find and the loci that other groups have found to be under recent positive selection.

Identification of local selective sweeps in human populations since the exodus from Africa
Åsa Johansson and Ulf Gyllensten,
Hereditas Volume 145, Issue 3, Pages 126-1372008
ABSTRACT: Selection on the human genome has been studied using comparative genomics and SNP architecture in the lineage leading to modern humans. In connection with the African exodus and colonization of other continents, human populations have adapted to a range of different environmental conditions. Using a new method that jointly analyses haplotype block length and allele frequency variation (FST) within and between populations, we have identified chromosomal regions that are candidates for having been affected by local selection. Based on 1.6 million SNPs typed in 71 individuals of African American, European American and Han Chinese descent, we have identified a number of genes and non-coding regions that are candidates for having been subjected to local positive selection during the last 100 000 years. Among these genes are those involved in skin pigmentation (SLC24A5) and diet adaptation (LCT). The list of genes implicated in these local selective sweeps overlap partly with those implicated in other studies of human populations using other methods, but show little overlap with those postulated to have been under selection in the 5–7 myr since the divergence of the ancestors of human and chimpanzee. Our analysis provides focal points in the genome for detailed studies of evolutionary events that have shaped human populations as they explored different regions of the world.

Tuesday, August 05, 2008

Religious diversity driven by disease prevalence

They find that countries with more diseases have more religions, presumably due to some kind of selection (individual, multi-level??) against out-group contact. This would seem to be a complex topic with plenty of potential confounds, many of which they seem to control for.
They invoke the optimal outbreeding hypothesis as to why out-group contact would be costly, but there is very scant evidence for this in humans. Then again, there's the paper I just posted about a few days ago that showed higher rates of obesity among multi-racial individuals, but I don't think that really counts in this context... Razib touches on some other potential examples here, well on this paper.

Assortative sociality, limited dispersal, infectious disease and the genesis of the global pattern of religion diversity
Corey L. Fincher, Randy Thornhill
Proceedings of the Royal Society, B First Cite
Abstract: Why are religions far more numerous in the tropics compared with the temperate areas? We propose, as an answer, that more religions have emerged and are maintained in the tropics because, through localized coevolutionary races with hosts, infectious diseases select for three anticontagion behaviours: in-group assortative sociality; out-group avoidance; and limited dispersal. These behaviours, in turn, create intergroup boundaries that effectively fractionate, isolate and diversify an original culture leading to the genesis of two or more groups from one. Religion is one aspect of a group's culture that undergoes this process. If this argument is correct then, across the globe, religion diversity should correlate positively with infectious disease diversity, reflecting an evolutionary history of antagonistic coevolution between parasites and hosts and subsequent religion genesis. We present evidence that supports this model: for a global sample of traditional societies, societal range size is reduced in areas with more pathogens compared with areas with few pathogens, and in contemporary countries religion diversity is positively related to two measures of parasite stress.

Saturday, August 02, 2008

Prevalence of obesity in multi-racial vs. mono-racial individuals

Despite the weird sounding title (why "ethnic admixture adults "? ... why not: "ethnically admixed adults" or something like that?) this paper (see below) examines quite an interesting question.
Do mixed-race individuals have a higher prevalence of obesity than single-race individuals?
First off, they mention that there is a high proportion (20%) of individuals who report two or more ethnicities in Hawaii, compared to the rest of the US (2%).
The introduction does not state why they expect to see the difference that they are looking for.
They have a humongous sample size (n=215,000), but the data is based on self-report which may bias the results.
The highest prevalence of overweight was for Hawaiian/Latino men (88%,) and black/Latina women (74.5%). The highest prevalence of obesity occurred in Hawaiian/Latino men (53.7%) and Hawaiian women (39.2%). The prevalence of obesity in men and women with Asian/white, Hawaiian/white, Hawaiian/Asian, Latina/white, and Hawaiian/Asian/white ethnic admixtures was significantly higher (P less than 0.0001) than the average prevalence of the ethnic groups with whom they share a common ethnicity/race.
and the money line:
Across all of the ethnic admixtures, the prevalences for both overweight and obesity were similar to or higher than the average of the prevalence estimates for their shared ethnicities; in contrast, none of the admixture prevalences were less than the average of their component ethnicities.
I can't believe they don't provide very much discussion about some of the potential mechanisms that would underlie their findings. They do find that:
"a high caloric intake (e.g., calories from fat and alcohol) and exercise did modestly decrease this difference" (referring to difference in prevalence between ethnic admixturesand monorace adults)"
There might be social and psychological factors that bi-racials experience more often than mono-racials, and this may negatively influence their health.
Nevertheless, this study is interesting and the finding merits future exploration.

The Prevalence of Obesity in Ethnic Admixture Adults
Cheryl L. Albright, Alana D. Steffen, Lynne R. Wilkens, Brian E. Henderson and Laurence N. Kolonel
Obesity (2008) 16 5, 1138–1143. doi:10.1038/oby.2008.31
Abstract: Objective: To determine whether the prevalence of obesity in ethnic admixture adults varies systematically from the average of the prevalence estimates for the ethnic groups with whom they share a common ethnicity.Methods and Procedures: The sample included 215,000 adults who reported one or more ethnicities, height, weight, and other characteristics through a mailed survey.Results: The highest age-adjusted prevalence of overweight (BMI 25) was in Hawaiian/Latino men (88% ; n = 41) and black/Latina women (74.5% ; n = 79), and highest obesity (BMI 30) rates were in Hawaiian/Latino men (53.7% ; n = 41) and Hawaiian women (39.2% , n = 1,247). The prevalence estimates for most admixed groups were similar to or higher than the average of the prevalences for the ethnic groups with whom they shared common ethnicities. For instance, the prevalence of overweight/obesity in five ethnic admixtures—Asian/white, Hawaiian/white, Hawaiian/Asian, Latina/white, and Hawaiian/Asian/white ethnic admixtures—was significantly higher (P less than 0.0001) than the average of the prevalence estimates for their component ethnic groups.Discussion: The identification of individuals who have a high-risk ethnic admixture is important not only to the personal health and well-being of such individuals, but could also be important to future efforts in order to control the epidemic of obesity in the United States.

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