Matthew Hansen

Going global by adapting local: A review of recent human adaptation

The spread of modern humans across the globe has led to genetic adaptations to diverse local environments. Recent developments in genomic technologies, statistical analyses, and expanded sampled populations have led to improved identification and fine-mapping of genetic variants associated with adaptations to regional living conditions and dietary practices. Ongoing efforts in sequencing genomes of indigenous populations, accompanied by the growing availability of “-omics” and ancient DNA data, promises a new era in our understanding of recent human evolution and the origins of variable traits and disease risks.

Loci associated with skin pigmentation identified in African populations

African genomics and skin color Skin color varies among human populations and is thought to be under selection, with light skin maximizing vitamin D production at higher latitudes and dark skin providing UV protection in equatorial zones. To identify the genes that give rise to the palette of human skin tones, Crawford et al. applied genome-wide analyses across diverse African populations (see the Perspective by Tang and Barsh). Genetic variants were identified with likely function in skin phenotypes. Comparison to model organisms verified a conserved function of MFSD12 in pigmentation. A global genetic panel was used to trace how alleles associated with skin color likely moved across the globe as humans migrated, both within and out of Africa. Science, this issue p. eaan8433; see also p. 867 Genome-wide analysis of 2000 Africans identifies and functionally characterizes pigmentation loci. INTRODUCTION Variation in pigmentation among human populations may reflect local adaptation to regional light environments, because dark skin is more photoprotective, whereas pale skin aids the production of vitamin D. Although genes associated with skin pigmentation have been identified in European populations, little is known about the genetic basis of skin pigmentation in Africans. RATIONALE Genetically and phenotypically diverse African populations are informative for mapping genetic variants associated with skin pigmentation. Analysis of the genetics of skin pigmentation in Africans informs upon melanocyte biology and the evolution of skin pigmentation in humans. RESULTS We observe extensive variation in skin pigmentation in Africa, with lowest melanin levels observed in southern African San hunter-gatherers and highest levels in East African Nilo-Saharan pastoralists. A genome-wide association study (GWAS) of 1570 Africans identified variants significantly associated with skin pigmentation, which clustered in four genomic regions that together account for almost 30% of the phenotypic variation. The most significantly associated single-nucleotide polymorphisms were at SLC24A5, a gene associated with pigmentation in Europeans. We show that SLC24A5 was introduced into East Africa >5 thousand years ago (ka) and has risen to high frequency. The second most significantly associated region is near the gene MFSD12. Using in vitro and in vivo analyses, we show that MFSD12 codes for a lysosomal protein that modifies pigmentation in human melanocytes, with decreased MFSD12 expression associated with darker pigmentation. We also show that genetic knockout of Mfsd12 affects pigmentation in mice. A third highly associated region encompasses a cluster of genes that play a role in ultraviolet (UV) response and DNA damage repair. We find the strongest associations in a regulatory region upstream of DDB1, the gene encoding damage-specific DNA binding protein 1, and that these variants are associated with increased expression of DDB1. The alleles associated with light pigmentation swept to near fixation outside of Africa due to positive selection, and we show that these lineages coalesce ~60 ka, corresponding with the time of migration of modern humans out of Africa. The fourth significantly associated region encompasses the OCA2 and HERC2 loci. We identify previously uncharacterized variants at HERC2 associated with the expression of OCA2. These variants arose independently from eye and skin pigmentation–associated variants in non-Africans. We also identify variants at OCA2 that are correlated with alternative splicing; alleles associated with light pigmentation are correlated with a shorter transcript, which lacks a transmembrane domain. CONCLUSION We identify previously uncharacterized genes and variants associated with skin pigmentation in ethnically diverse Africans. These genes have diverse functions, from repairing UV damage to playing important roles in melanocyte biology. We show that both dark and light pigmentation alleles arose before the origin of modern humans and that both light and dark pigmented skin has continued to evolve throughout hominid history. We show that variants associated with dark pigmentation in Africans are identical by descent in South Asian and Australo-Melanesian populations. This study sheds light on the evolutionary history, and adaptive significance, of skin pigmentation in humans. GWAS and functional assays illuminate the genetic basis of pigmentation in Africa. A GWAS identified four genomic regions associated with skin pigmentation in Africa. Functional assays in melanocytes and mice characterized their impact on skin pigmentation. Evolutionary genetic analyses revealed that most derived variants evolved before the origin of modern humans. Ma, million years ago. Despite the wide range of skin pigmentation in humans, little is known about its genetic basis in global populations. Examining ethnically diverse African genomes, we identify variants in or near SLC24A5, MFSD12, DDB1, TMEM138, OCA2, and HERC2 that are significantly associated with skin pigmentation. Genetic evidence indicates that the light pigmentation variant at SLC24A5 was introduced into East Africa by gene flow from non-Africans. At all other loci, variants associated with dark pigmentation in Africans are identical by descent in South Asian and Australo-Melanesian populations. Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of ultraviolet response genes under selection in Eurasians.

Mimosa: Mixture model of co-expression to detect modulators of regulatory interaction

BackgroundFunctionally related genes tend to be correlated in their expression patterns across multiple conditions and/or tissue-types. Thus co-expression networks are often used to investigate functional groups of genes. In particular, when one of the genes is a transcription factor (TF), the co-expression-based interaction is interpreted, with caution, as a direct regulatory interaction. However, any particular TF, and more importantly, any particular regulatory interaction, is likely to be active only in a subset of experimental conditions. Moreover, the subset of expression samples where the regulatory interaction holds may be marked by presence or absence of a modifier gene, such as an enzyme that post-translationally modifies the TF. Such subtlety of regulatory interactions is overlooked when one computes an overall expression correlation.ResultsHere we present a novel mixture modeling approach where a TF-Gene pair is presumed to be significantly correlated (with unknown coefficient) in an (unknown) subset of expression samples. The parameters of the model are estimated using a Maximum Likelihood approach. The estimated mixture of expression samples is then mined to identify genes potentially modulating the TF-Gene interaction. We have validated our approach using synthetic data and on four biological cases in cow, yeast, and humans.ConclusionsWhile limited in some ways, as discussed, the work represents a novel approach to mine expression data and detect potential modulators of regulatory interactions.

Sex-Biased Networks and Nodes of Sexually Antagonistic Conflict in Drosophila

Sexual antagonism, or conflict, can occur when males and females harbor opposing reproductive strategies. The large fraction of sex-biased genes in genomes present considerable opportunities for conflict to occur, suggesting that sexual antagonism may potentially be a general phenomenon at the molecular level. Here, we employ a novel strategy to identify potential nodes of sexual conflict in Drosophila melanogaster by coupling male, female, and sex-unbiased networks derived from genome-wide expression data with available genetic and protein interaction data. We find that sex-biased networks comprise a large fraction (~1/3) of the total interaction network with the male network possessing nearly twice the number of nodes (genes) relative to the female network. However, there are far less edges or interaction partners among male relative to female subnetworks as seen in their power law distributions. We further identified 598 sex-unbiased genes that can act as indirect nodes of interlocus sexual conflict as well as 271 direct nodal pairs of potential conflict between male- and female-biased genes. The pervasiveness of such potentially conflicting nodes may explain the rapid evolution of sex-biased as well as non-sex-biased genes via this molecular mechanism of sexual selection even among taxa such as Drosophila that are nominally sexually dimorphic.

Genetic hitchhiking and population bottlenecks contribute to prostate cancer disparities in men of African descent

Prostate cancer incidence and mortality rates in African and African American men are greatly elevated compared with other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to prostate cancer disparities is unclear. Here, we investigated the population structure of 68 previously reported GWAS loci and calculated genetic disparity contribution statistics to identify SNPs that contribute the most to differences in prostate cancer risk across populations. By integrating GWAS results with allele frequency data, we generated genetic risk scores for 45 African and 19 non-African populations. Tests of natural selection were used to assess why some SNPs have large allele frequency differences across populations. We report that genetic predictions of prostate cancer risks are highest for West African men and lowest for East Asian men. These differences may be explained by the out-of-Africa bottleneck and natural selection. A small number of loci appear to drive elevated prostate cancer risks in men of African descent, including rs9623117, rs6983267, rs10896449, rs10993994, and rs817826. Although most prostate cancer-associated loci are evolving neutrally, there are multiple instances where alleles have hitchhiked to high frequencies with linked adaptive alleles. For example, a protective allele at 2q37 appears to have risen to high frequency in Europe due to selection acting on pigmentation. Our results suggest that evolutionary history contributes to the high rates of prostate cancer in African and African American men.Significance: A small number of genetic variants cause an elevated risk of prostate cancer in men of West African descent. Cancer Res; 78(9); 2432-43. ©2018 AACR.

Abstract A33: Population and evolutionary genomics of prostate cancer-associated variants: implications for health disparities in men of African descent

To determine why African men are more likely to suffer from prostate cancer (CaP), we integrated GWAS results and scans of selection with allele frequency data from 64 global populations. Despite substantial overlap in genetic risk scores across populations, we find that predicted CaP risk is highest in West Africans and that a small number of loci drive these differences in risk. There is a strong concordance between genetic risk scores and clinical estimates of CaP mortality. Although most CaP-associated loci are evolving neutrally, we find multiple instances where alleles have hitchhiked to high frequencies with linked locally adaptive alleles. Citation Format: Joseph Lachance, Ali Berens, Matthew Hansen, Andrew Teng, Sarah Tishkoff, Timothy Rebbeck. Population and evolutionary genomics of prostate cancer-associated variants: implications for health disparities in men of African descent [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A33.

Mimosa: mixture model of co-expression to detect modulators of regulatory interaction

Functionally related genes tend to be correlated in their expression patterns across multiple conditions and/or tissue-types. Thus co-expression networks are often used to investigate functional groups of genes. In particular, when one of the genes is a transcription factor (TF), the co-expression-based interaction is interpreted, with caution, as a direct regulatory interaction. However, any particular TF, and more importantly, any particular regulatory interaction, is likely to be active only in a subset of experimental conditions. Moreover, the subset of expression samples where the regulatory interaction holds may be marked by presence or absence of a modifier gene, such as an enzyme that post-translationally modifies the TF. Such subtlety of regulatory interactions is overlooked when one computes an overall expression correlation. Here we present a novel mixture modeling approach where a TF-Gene pair is presumed to be significantly correlated (with unknown coefficient) in a (unknown) subset of expression samples. The parameters of the model are estimated using a Maximum Likelihood approach. The estimated mixture of expression samples is then mined to identify genes potentially modulating the TF-Gene interaction. We have validated our approach using synthetic data and on three biological cases in cow and in yeast. While limited in some ways, as discussed, the work represents a novel approach to mine expression data and detect potential modulators of regulatory interactions.