Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. ...Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long reads: their purpose and place Pollard, Martin O; Gurdasani, Deepti; Mentzer, Alexander J ...
Human molecular genetics,
08/2018, Letnik:
27, Številka:
R2
Journal Article
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Abstract
In recent years long-read technologies have moved from being a niche and specialist field to a point of relative maturity likely to feature frequently in the genomic landscape. Analogous to ...next generation sequencing, the cost of sequencing using long-read technologies has materially dropped whilst the instrument throughput continues to increase. Together these changes present the prospect of sequencing large numbers of individuals with the aim of fully characterizing genomes at high resolution. In this article, we will endeavour to present an introduction to long-read technologies showing: what long reads are; how they are distinct from short reads; why long reads are useful and how they are being used. We will highlight the recent developments in this field, and the applications and potential of these technologies in medical research, and clinical diagnostics and therapeutics.
Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present ...929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations.
Little is known regarding the first people to enter the Americas and their genetic legacy. Genomic analysis of the oldest human remains from the Americas showed a direct relationship between a ...Clovis-related ancestral population and all modern Central and South Americans as well as a deep split separating them from North Americans in Canada. We present 91 ancient human genomes from California and Southwestern Ontario and demonstrate the existence of two distinct ancestries in North America, which possibly split south of the ice sheets. A contribution from both of these ancestral populations is found in all modern Central and South Americans. The proportions of these two ancestries in ancient and modern populations are consistent with a coastal dispersal and multiple admixture events.
Polygenic prediction of type 2 diabetes (T2D) in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of T2D from Africa and the poor ...transferability of European-derived polygenic risk scores (PRSs) in diverse ethnicities. We set out to evaluate if African American, European, or multiethnic-derived PRSs would improve polygenic prediction in continental Africans.
Using the PRSice software, ethnic-specific PRSs were computed with weights from the T2D GWAS multiancestry meta-analysis of 228,499 case and 1,178,783 control subjects. The South African Zulu study (n = 1,602 case and 981 control subjects) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis were conducted in the Africa America Diabetes Mellitus (AADM) study (n = 2,148 case and 2,161 control subjects).
The discriminatory ability of the African American and multiethnic PRSs was similar. However, the African American-derived PRS was more transferable in all the countries represented in the AADM cohort and predictive of T2D in the country combined analysis compared with the European and multiethnic-derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (odds ratio 3.63; 95% CI 2.19-4.03; P = 2.79 × 10-17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier than those in the first decile.
African American-derived PRS enhances polygenic prediction of T2D in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in T2D.
Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across ...populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23-0.28, p < 1.9 × 10
). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.
A genomic history of Aboriginal Australia Malaspinas, Anna-Sapfo; Westaway, Michael C; Muller, Craig ...
Nature,
10/2016, Letnik:
538, Številka:
7624
Journal Article
Recenzirano
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The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 ...Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.
Previous genome-wide association studies (GWAS) of HIV-1–infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the ...phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protectiveCCR5Δ32allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation—mostly in the HLA and CCR5 regions—explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.
The peroxisome proliferator-activated receptor-γ gene (PPARG) has been implicated in the etiology of type 2 diabetes mellitus and has been investigated in numerous epidemiologic studies. In this ...Human Genome Epidemiology review, the authors assessed this relation in an updated meta-analysis of 60 association studies. Electronic literature searches were conducted on September 14, 2009. Population-based cohort, case-control, cross-sectional, or genome-wide association studies reporting associations between the PPARG Pro12Ala gene variant (rs1801282) and type 2 diabetes were included. An updated literature-based meta-analysis involving 32,849 type 2 diabetes cases and 47,456 controls in relation to the PPARG Pro12Ala variant was conducted. The combined overall odds ratio, calculated by per-allele genetic model random-effects meta-analysis for type 2 diabetes and the Pro12Ala polymorphism, was 0.86 (95% confidence interval: 0.81, 0.90). The analysis indicated a moderate level of heterogeneity attributable to genuine variation in gene effect size (I2 = 37%). This may reflect the variation observed between ethnic populations and/or differences in body mass index. Work on PPARG Pro12Ala should now focus on the observed heterogeneity in the magnitude of the association between populations. Further investigations into gene-gene and gene-environment interactions may prove enlightening.
Urban living is associated with unhealthy lifestyles that can increase the risk of cardiometabolic diseases. In sub-Saharan Africa (SSA), where the majority of people live in rural areas, it is still ...unclear if there is a corresponding increase in unhealthy lifestyles as rural areas adopt urban characteristics. This study examines the distribution of urban characteristics across rural communities in Uganda and their associations with lifestyle risk factors for chronic diseases.
Using data collected in 2011, we examined cross-sectional associations between urbanicity and lifestyle risk factors in rural communities in Uganda, with 7,340 participants aged 13 y and above across 25 villages. Urbanicity was defined according to a multi-component scale, and Poisson regression models were used to examine associations between urbanicity and lifestyle risk factors by quartile of urbanicity. Despite all of the villages not having paved roads and running water, there was marked variation in levels of urbanicity across the villages, largely attributable to differences in economic activity, civil infrastructure, and availability of educational and healthcare services. In regression models, after adjustment for clustering and potential confounders including socioeconomic status, increasing urbanicity was associated with an increase in lifestyle risk factors such as physical inactivity (risk ratio RR: 1.19; 95% CI: 1.14, 1.24), low fruit and vegetable consumption (RR: 1.17; 95% CI: 1.10, 1.23), and high body mass index (RR: 1.48; 95% CI: 1.24, 1.77).
This study indicates that even across rural communities in SSA, increasing urbanicity is associated with a higher prevalence of lifestyle risk factors for cardiometabolic diseases. This finding highlights the need to consider the health impact of urbanization in rural areas across SSA. Please see later in the article for the Editors' Summary.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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