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The inclusion of ethnicity in equations for estimating the glomerular filtration rate (eGFR) from serum creatinine levels has been challenged since ethnicity is socially defined and therefore a poor proxy for biological differences. We hypothesized that genetic ancestry (GA) would be more strongly associated with creatinine levels among healthy individuals than self-identified ethnicity. We studied a diverse cohort of 35,590 participants characterized as part of the UK Biobank, grouped by self-reported ethnicity: Black, East Asian, Mixed, Other, South Asian, and White. We used multivariable modeling to test for associations between ethnicity, GA, socioeconomic deprivation, and serum creatinine levels, including covariates for age, sex, height, and body mass index. Model fit comparisons and relative importance analysis were used to compare the effects of ethnicity and GA on creatinine levels. Black ethnicity shows a positive effect on participant serum creatinine levels (β = 9.36 ± 0.38), whereas East Asian (β = -1.80 ± 0.66) and South Asian (β = -0.28 ± 0.36) ethnicity show negative effects on creatinine. Male sex (β = 17.69 ± 0.34) and height (β = 0.13 ± 0.02) also show high positive associations with creatinine levels, while socioeconomic deprivation (β = -0.04 ± 0.04) shows no significant association. African ancestry has the highest association (β = 13.81 ± 0.52) with creatinine levels. Overall, GA (9.06%) explains significantly more of the variation in creatinine levels than ethnicity (4.96%), with African ancestry (6.36%) alone explaining more of the variation than ethnicity. We found that GA explains more of the variation in serum creatinine levels than socioeconomic deprivation, suggesting the possibility that ethnic differences in creatinine are shaped by genetic rather than social factors.

Background Type 2 diabetes (T2D) is a complex common disease that disproportionately impacts minority ethnic groups in the United Kingdom (UK). Socioeconomic deprivation (SED) is widely considered as a potential explanation for T2D ethnic disparities in the UK, whereas the effect of genetic ancestry (GA) on such disparities has yet to be studied. Methods We leveraged data from the UK Biobank prospective cohort study, with participants enrolled between 2006 and 2010, to model the relationship between SED (Townsend index), GA (clustering principal components of whole genome genotype data), and T2D status (ICD-10 codes) across the three largest ethnic groups in the UK – Asian, Black, and White – using multivariable logistic regression. Findings The Asian group shows the highest T2D prevalence (17·9%), followed by the Black (11·7%) and White (5·5%) ethnic groups. We find that both SED (OR: 1·11, 95% CI: 1·10–1·11) and non-European GA (OR South Asian versus European: 4·37, 95% CI: 4·10–4·66; OR African versus European: 2·52, 95% CI: 2·23–2·85) are significantly associated with the observed T2D disparities. GA and SED show significant interaction effects on T2D, with SED being a relatively greater risk factor for T2D for individuals with South Asian and African ancestry, compared to those with European ancestry. Interpretation The significant interactions between SED and GA underscore how the effects of environmental risk factors can differ among ancestry groups, suggesting the need for group-specific interventions. Funding This work was supported by the National Institutes of Health (NIH) Distinguished Scholars Program (DSP) to LMR and the Division of Intramural Research (DIR) of the National Institute on Minority Health and Health Disparities (NIMHD) at NIH.

Insertional activity of transposable elements (TEs) has had a major impact on the human genome; approximately one-half to two-thirds of the genome sequence is likely to be derived from TE insertions. Several families of human TEs - primarily Alu, L1 and SVA - continue to actively transpose, thereby generating insertional polymorphisms among individual genomes. The impact that TE insertions have on their human hosts' fitness, and accordingly the role that natural selection plays in shaping patterns of TE polymorphisms among populations, have yet to be systematically evaluated using whole genome sequence data. We present here a population genomic study of the effects of natural selection on human genetic variation that results from the recent activity of TEs. We developed a genome-wide scan for selection on human TE polymorphisms and applied it to a dataset of 14,384 locus-specific TE insertions characterized for 1511 individuals from 15 populations. Our TE selection scan looks for anomalously high population-specific TE insertion allele frequencies that are consistent with the action of positive (adaptive) selection. To control for the effects of demographic history, we compared the observed patterns of population-specific TE insertion allele frequencies to a neutral evolutionary model generated using time forward simulation of TE insertion allele frequencies among human population groups. This approach uncovered seven cases of polymorphic TE insertions that appear to have increased in frequency within specific human populations owing to the effects of positive selection. Five of the seven putatively selected TE insertions map to tissue-specific enhancers, and two cases correspond to expression quantitative trait loci that are associated with inter-individual gene regulatory differences. This study represents the first report of recent, local adaptation acting on polymorphic human TEs.

A convergence of novel genome analysis technologies is enabling population genomic studies of human transposable elements (TEs). Population surveys of human genome sequences have uncovered thousands of individual TE insertions that segregate as common genetic variants, i.e. TE polymorphisms. These recent TE insertions provide an important source of naturally occurring human genetic variation. Investigators are beginning to leverage population genomic data sets to execute genome-scale association studies for assessing the phenotypic impact of human TE polymorphisms. For example, the expression quantitative trait loci (eQTL) analytical paradigm has recently been used to uncover hundreds of associations between human TE insertion variants and gene expression levels. These include population-specific gene regulatory effects as well as coordinated changes to gene regulatory networks. In addition, analyses of linkage disequilibrium patterns with previously characterized genome-wide association study (GWAS) trait variants have uncovered TE insertion polymorphisms that are likely causal variants for a variety of common complex diseases. Gene regulatory mechanisms that underlie specific disease phenotypes have been proposed for a number of these trait associated TE polymorphisms. These new population genomic approaches hold great promise for understanding how ongoing TE activity contributes to functionally relevant genetic variation within and between human populations.

Uniparental genetic markers, mitochondrial DNA (mtDNA) and Y chromosomal DNA, are widely used for the inference of human ancestry. However, the resolution of ancestral origins based on mtDNA haplotypes is limited by the fact that such haplotypes are often found to be distributed across wide geographical regions. We have addressed this issue here by combining two sources of ancestry information that have typically been considered separately: historical records regarding population origins and genetic information on mtDNA haplotypes. To combine these distinct data sources, we applied a Bayesian approach that considers historical records, in the form of prior probabilities, together with data on the geographical distribution of mtDNA haplotypes, formulated as likelihoods, to yield ancestry assignments from posterior probabilities. This combined evidence Bayesian approach to ancestry assignment was evaluated for its ability to accurately assign sub-continental African ancestral origins to Afro-Colombians based on their mtDNA haplotypes. We demonstrate that the incorporation of historical prior probabilities via this analytical framework can provide for substantially increased resolution in sub-continental African ancestry assignment for members of this population. In addition, a personalized approach to ancestry assignment that involves the tuning of priors to individual mtDNA haplotypes yields even greater resolution for individual ancestry assignment. Despite the fact that Colombia has a large population of Afro-descendants, the ancestry of this community has been understudied relative to populations with primarily European and Native American ancestry. Thus, the application of the kind of combined evidence approach developed here to the study of ancestry in the Afro-Colombian population has the potential to be impactful. The formal Bayesian analytical framework we propose for combining historical and genetic information also has the potential to be widely applied across various global populations and for different genetic markers.

It was previously thought that epigenetic histone modifications of mammalian transposable elements (TEs) serve primarily to defend the genome against deleterious effects associated with their activity. However, we recently showed that, genome-wide, human TEs can also be epigenetically modified in a manner consistent with their ability to regulate host genes. Here, we explore the ability of TE sequences to epigenetically regulate individual human genes by focusing on the histone modifications of promoter sequences derived from TEs. We found 1520 human genes that initiate transcription from within TE-derived promoter sequences. We evaluated the distributions of eight histone modifications across these TE-promoters, within and between the GM12878 and K562 cell lines, and related their modification status with the cell-type specific expression patterns of the genes that they regulate. TE-derived promoters are significantly enriched for active histone modifications, and depleted for repressive modifications, relative to the genomic background. Active histone modifications of TE-promoters peak at transcription start sites and are positively correlated with increasing expression within cell lines. Furthermore, differential modification of TE-derived promoters between cell lines is significantly correlated with differential gene expression. LTR-retrotransposon derived promoters in particular play a prominent role in mediating cell-type specific gene regulation, and a number of these LTR-promoter genes are implicated in lineage-specific cellular functions. The regulation of human genes mediated by histone modifications targeted to TE-derived promoters is consistent with the ability of TEs to contribute to the epigenomic landscape in a way that provides functional utility to the host genome.

Transposable elements (TEs) are abundant in mammalian genomes and have potentially contributed to their hosts' evolution by providing novel regulatory or coding sequences. We surveyed different classes of regulatory region in the human genome to assess systematically the potential contribution of TEs to gene regulation. Almost 25% of the analyzed promoter regions contain TE-derived sequences, including many experimentally characterized cis-regulatory elements. Scaffold/matrix attachment regions (S/MARs) and locus control regions (LCRs) that are involved in the simultaneous regulation of multiple genes also contain numerous TE-derived sequences. Thus, TEs have probably contributed substantially to the evolution of both gene-specific and global patterns of human gene regulation.

In overlapping genes, the same DNA sequence codes for two proteins using different reading frames. Analysis of overlapping genes can help in understanding the mode of evolution of a coding region from noncoding DNA. We identified 71 pairs of convergent genes, with overlapping 3' ends longer than 15 nucleotides, that are conserved in at least two prokaryotic genomes. Among the overlap regions, we observed a statistically significant bias towards the 123:132 phase (i.e. the second codon base in one gene facing the degenerate third position in the second gene). This phase ensures the least mutual constraint on nonconservative amino acid replacements in both overlapping coding sequences. The excess of this phase is compatible with directional (positive) selection acting on the overlapping coding regions. This could be a general evolutionary mode for genes emerging from noncoding sequences, in which the protein sequence has not been subject to selection.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ancient ABC transporter superfamily. Most ABC proteins are transporters that operate via an alternating access mechanism, except for CFTR which is best known for its activity as a chloride channel. We compared CFTR protein sequences to those of its closest mammalian paralogs, ABCC4 and ABCC5, and used the statistical analysis program DIVERGE to analyze a CFTR-ABCC4-ABCC5 multiple sequence alignment to identify residues (called Type II divergent residues) most likely to be involved in the evolutionary transition from transporter to channel.The Type II divergent amino acids were further divided into three groups based on their functional differences. Group I: charged residues that contribute to maintaining CFTR's open pore architecture, including R117, R334, and R352. CFTR channels with mutations at these sites exhibited multiple open states with significantly shorter burst durations compared to WT-CFTR. Group II: sites where mutation resulted in no detectable current in Xenopus oocytes and loss of surface expression in HEK293 cells, including P140. Group III: sites where mutation did not alter single channel behavior or block by glibenclamide, including N187, T262, Q1038, K1060, N1148. These data suggest that Type II divergent amino acids may be key players in CFTR channel activity, at least in part by converting the conformational changes of a transporter into an open permeation pathway with a stable open state. This analysis sets the stage for understanding the evolutionary and functional relationships that make CFTR a unique ABC superfamily protein. (NIH-2R56DK056481-07)