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.

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.

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.

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.

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.