Biology subjects

Shriner, D.

Publications and source records attributed to Shriner, D..

9 recordsLinked to original sources

bioRxiv2025

Subcontinental Genetic Diversity in the All of Us Research Program: Implications for Biomedical Research

The All of Us Research Program (All of Us) seeks to accelerate biomedical research and address the underrepresentation of minorities by recruiting over one million ethnically diverse participants across the United States. A key question is how self-identification with discrete, predefined race and ethnicity categories compares to genetic diversity at continental and subcontinental levels. To contextualize the genetic diversity in All of Us, we analyzed [~]2 million common variants from 230,016 unrelated whole genomes using classical population genetics methods, alongside reference panels such as the 1000 Genomes Project, Human Genome Diversity Project, and Simons Genome Diversity Project. Our analysis reveals that participants within self-identified race and ethnicity groups exhibit a gradient of genetic diversity rather than discrete clusters. The distributions of continental and subcontinental ancestries show considerable variation within race and ethnicity, both nationally and across states, reflecting the historical impacts of U.S. colonization, the transatlantic slave trade, and recent migrations. All of Us samples filled most gaps along the top five principal components of genetic diversity in current global reference panels. Notably, "Hispanic or Latino" participants spanned much of the three-way (African, Native American, and European) admixture spectrum. Ancestry was significantly associated with body mass index (BMI) and height, even after adjusting for socio-environmental covariates. In particular, West-Central and East African ancestries showed opposite associations with BMI. This study emphasizes the importance of assessing subcontinental ancestries, as the continental approach is insufficient to control for confounding in genetic association studies.

genomics↗

bioRxiv2023

Random forest classifiers trained on simulated data enable accurate short read-based genotyping of structural variants in the alpha globin region at Chr16p13.3

In regions where reads dont align well to a reference, it is generally difficult to characterize structural variation using short read sequencing. Here, we utilize machine learning classifiers and short sequence reads to genotype structural variants in the alpha globin locus on chromosome 16, a medically-relevant region that is challenging to genotype in individuals. Using models trained only with simulated data, we accurately genotype two hard-to-distinguish deletions in two separate human cohorts. Furthermore, population allele frequencies produced by our methods across a wide set of ancestries agree more closely with previously-determined frequencies than those obtained using currently available genotyping software.

bioinformatics↗

bioRxiv2022

Unappreciated Subcontinental Admixture in Europeans and European Americans: Implications for Genetic Epidemiology Studies

European-ancestry populations are recognized as stratified but not as admixed, implying that residual confounding by locus-specific ancestry can affect studies of association, polygenic adaptation, and polygenic risk scores. We integrated individual-level genome-wide data from ~19,000 European-ancestry individuals across 79 European populations and five European American cohorts. We generated a new reference panel that captures ancestral diversity missed by both the 1000 Genomes and Human Genome Diversity Projects. Both Europeans and European-Americans are admixed at subcontinental level, with admixture dates differing among subgroups of European Americans. After adjustment for both genome-wide and locus-specific ancestry, associations between a highly differentiated variant in LCT (rs4988235) and height or LDL-cholesterol were confirmed to be false positives whereas the association between LCT and body mass index was genuine. We provide formal evidence of subcontinental admixture in individuals with European ancestry, which, if not properly accounted for, can produce spurious results in genetic epidemiology studies.

evolutionary biology↗

bioRxiv2021

KTD1 is a yeast defense factor against K28 killer toxin

Secreted protein toxins are widely used weapons in conflicts between organisms. Killer yeast produce killer toxins that inhibit the growth of nearby sensitive yeast. We investigated variation in resistance to the killer toxin K28 across diverse natural isolates of the Saccharomyces cerevisiae population and discovered a novel defense factor, which we named KTD1, that is an important determinant of K28 toxin resistance. KTD1 is a member of the DUP240 gene family of unknown function. We uncovered a putative role of DUP240 proteins in killer toxin defense and identified a region that is undergoing rapid evolution and is critical to KTD1s protective ability. Our findings implicate KTD1 as a key factor in the defense against killer toxin K28.

genetics↗

bioRxiv2020

GWAS in Africans identifies novel lipids loci and demonstrates heterogenous association within Africa

BackgroundSerum lipids are biomarkers of cardiometabolic disease risk, and understanding the genomic factors contributing to their distribution has been of considerable interest. Large genome-wide association studies (GWAS) have identified over 150 lipids loci; however, GWAS of Africans (AF) are rare. Given the genomic diversity among those of African ancestry, it is expected that a GWAS in Africans could identify novel lipids loci. While GWAS have been conducted in African Americans (AA), such studies are not proxies for studies in continental Africans due to the drastically different environmental context. Therefore, we conducted a GWAS of 4,317 Africans enrolled in the Africa America Diabetes Mellitus study. Methods and ResultsWe used linear mixed models of the inverse normal transformations of covariate-djusted residuals of high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), total cholesterol (CHOL), triglycerides (TG), and TG/HDLC, with adjustment for three principal components and the random effect of relatedness. Replication of loci associated at p<5x10-8 was attempted in 9,542 AA. Meta-analysis of AF and AA was also conducted. We also conducted analyses that excluded the relatively small number of East Africans. We evaluated known lipids loci in Africans using both exact replication and "local" replication, which accounts for interethnic differences in linkage disequilibrium. In our main analysis, we identified 23 novel associations in Africans. Of the 14 of these that were able to be tested in AA, two associations replicated (GPNMB-TG and ENPP1-TG). Two additional novel loci were discovered upon meta-analysis with AA (rs138282551-TG and TLL2-CHOL). Analyses considering only those with predominantly West African ancestry (Nigeria, Ghana, and AA) yielded new insights: ORC5-LDLC and chr20:60973327-CHOL. ConclusionsWhile functional work will be useful to confirm and understand the biological mechanisms underlying these associations, this study demonstrates the utility of conducting large-scale genomic analyses in Africans for discovering novel loci. The functional significance of some of these loci in relation to lipids remains to be elucidated, yet some have known connections to lipids pathways. For instance, rs147706369 (intronic, TLL2) alters a regulatory motif for sterol regulatory element-binding proteins (SREBPs), which are a family of transcription factors that control the expression of a range of enzymes involved in cholesterol, fatty acid, and triglyceride synthesis.

genomics↗

bioRxiv2020

Genetic Risk Scores for Cardiometabolic Traits in Sub-Saharan African Populations

There is growing support for the use of genetic risk scores (GRS) in routine clinical settings. Due to the limited diversity of current genomic discovery samples, there are concerns that the predictive power of GRS will be limited in non-European ancestry populations. Here, we evaluated the predictive utility of GRS for 12 cardiometabolic traits in sub-Saharan Africans (AF; n=5200), African Americans (AA; n=9139), and European Americans (EA; n=9594). GRS were constructed as weighted sums of the number of risk alleles. Predictive utility was assessed using the additional phenotypic variance explained and increase in discriminatory ability over traditional risk factors (age, sex and BMI), with adjustment for ancestry-derived principal components. Across all traits, GRS showed upto a 5-fold and 20-fold greater predictive utility in EA relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percent increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EA, 26.6% to 65.8% among AA, and 2.4% to 37.5% among AF. These differences were recapitulated in the discriminatory power, whereby the predictive utility of GRS was 4-fold greater in EA relative to AA and up to 44-fold greater in EA relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EA. This work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiethnic populations in genomic studies to ensure equitable clinical translation of GRS. Key MessagesO_LIGenetic Risk Score (GRS) prediction is markedly poorer in sub-Saharan Africans compared with African Americans and European Americans C_LIO_LITo ensure equitable clinical translation of GRS, there is need need to improve representation of multiethnic populations in genomic studies C_LI

genomics↗

bioRxiv2019

A Novel Type 2 Diabetes Locus in sub-Saharan Africans, ZRANB3, is Implicated in Beta Cell Proliferation

Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report the largest genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyzed ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. TCF7L2 rs7903156 was the most significant locus (p=7.288 x 10-13). We identified a novel genome wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP chr2:136064024, T allele frequency=0.034, p=2.831x10-9). Knockdown of the zebrafish ortholog resulted in reduction in pancreatic beta cell number in the developing organism, suggesting a potential mechanism for its effect on glucose hemostasis. We also showed transferability in our study of 32 established T2D loci. Our findings provide evidence of a novel candidate T2D locus and advance understanding of the genetics of T2D in non-European ancestry populations.

genetics↗

bioRxiv2018

Ancestral heterogeneity of ancient Eurasians

Supervised clustering or projection analysis is a staple technique in population genetic analysis. The utility of this technique depends critically on the reference panel. The most commonly used reference panel in the analysis of ancient DNA to date is based on the Human Origins array. We previously described a larger reference panel that captures more ancestries on the global level. Here, we reanalyzed DNA data from 279 ancient Eurasians using our reference panel. We found substantially more ancestral heterogeneity than has been reported. Our reanalysis provides evidence against a resurgence of Western hunter-gatherer ancestry in the Middle to Late Neolithic and evidence for a common ancestor of farmers characterized by Western Asian ancestry, a transition of the spread of agriculture from demic to cultural diffusion, at least two migrations between the Pontic-Caspian steppes and Bronze Age Europe, and a sub-Saharan African component in Natufians that localizes to present-day southern Ethiopia.

genetics↗

bioRxiv2017

Whole genome sequence-based haplotypes reveal single origin of the sickle allele during the Holocene Wet Phase

Five classical designations of sickle haplotypes are based on the presence/absence of restriction sites and named after ethnic groups or geographic regions from which patients originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation. We investigated the origins of the sickle mutation using whole genome sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. We defined a new haplotypic classification using 27 polymorphisms in linkage disequilibrium with rs334. Network analysis revealed a common haplotype that differed from the ancestral haplotype only by the derived sickle mutation at rs334 and correlated collectively with the Central African Republic/Bantu, Cameroon, and Arabian/Indian designations. Other haplotypes were derived from this haplotype and fell into two clusters, one comprised of haplotypes correlated with the Senegal designation and the other comprised of haplotypes correlated with both the Benin and Senegal designations. The near-exclusive presence of the original sickle haplotype in the Central African Republic, Kenya, Uganda, and South Africa is consistent with this haplotype predating the Bantu Expansion. Modeling of balancing selection indicated that the heterozygote advantage was 15.2%, an equilibrium frequency of 12.0% was reached after 87 generations, and the selective environment predated the mutation. The posterior distribution of the ancestral recombination graph yielded an age of the sickle mutation of 259 generations, corresponding to 7,300 years and the Holocene Wet Phase. These results clarify the origin of the sickle allele and improve and simplify the classification of sickle haplotypes.

genetics↗