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Thread: Uganda Genome Resource Enables Insights into Pop. Hist. & Genomic Discovery in Africa

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    Uganda Genome Resource Enables Insights into Pop. Hist. & Genomic Discovery in Africa

    Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa
    Deepti Gurdasani et al.


    Highlights

    • The Uganda Genome Resource comprises genetic and phenotypic data on 6,400 individuals
    • Ugandans show geographically correlated genetic substructure and complex admixture
    • The Uganda sequence panel substantially improves imputation in African populations
    • The Uganda Genome Resource enables novel discovery of loci associated with traits





    Summary:

    Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.




    Graphical Abstract:

     

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    The paper is unfortunately behind a ppv wall, here's a few highlighted insights from recent news-releases...

    Largest ever genome study of Africans could lead to new disease treatments
    London School of Hygiene & Tropical Medicine (31 October 2019):
     
    Around a quarter of the genetic variation identified in the new study, published in the journal Cell, had not been discovered before. The study also found a higher level of genetic diversity in the Ugandan population than is seen in similar studies of European populations.

    The research was carried out by partners including the London School of Hygiene & Tropical Medicine (LSHTM) and MRC/UVRI & LSHTM Uganda Research Unit.

    Lead author Dr Deepti Gurdasani from Queen Mary University of London said: “Most population genetics studies involve Western populations. We developed a rich, diverse resource using genome wide data from 6,400 Africans, including whole genome sequencing of nearly 2,000 people. Other researchers can use this data to improve the detection of genetic causes of disease – particularly those that disproportionately affect Africans and people with African ancestry.

    Modern Uganda appears to be a complex mosaic of many different communities that have migrated from surrounding regions – and from Europe and the Middle East. These migrations appear to have taken place regularly and date from just 300 years ago to around 2500 BC.

    The research team collected and analysed genome-wide data from 6,400 people from a rural community in Uganda. The team also incorporated data on 14,000 individuals from different parts of Africa. This allowed them to examine genetic determinants of traits within the population.

    The combined study identified new genes associated with several diseases. These included ten new associations, of which nine are only found in Africans and would therefore not have been found in even the largest study involving Europeans.

    These discoveries included a genetic variant that causes thalassemia present in 22% of Africans, which is associated with glycated haemoglobin, an indicator commonly used in the diagnosis of diabetes. This particular variant is thought to have become more frequent among African populations because it can prevent severe malaria.

    Lead author Dr Segun Fatumo, Assistant Professor of Genetic Epidemiology & Bioinformatics at LSHTM and a senior scientist at MRC/UVRI & LSHTM Uganda Research Unit, said: “Our study is a major initiative at the cutting-edge of precision medicine. Discovering novel genes that are linked to common and complex diseases found in Africa could pave the way for new ways to diagnose, prevent and treat them. I am delighted to have played a lead role in identifying them.”

    As glycated haemoglobin levels are often used to diagnose diabetes, the authors say it is possible that diabetes may be misdiagnosed in some Africans if glycated haemoglobin is used as a diagnostic tool.

    The Ugandan data also revealed differences in the importance of heritability for certain characteristics – including height and cholesterol levels. The latter could reflect differences in genetic and dietary factors that influence these characteristics across different populations.

    Lead investigator, Professor Pontiano Kaleebu, who is the Director of the MRC/Uganda Virus Research Institute & LSHTM Uganda Research Unit, said: “Africa is central to our understanding of human origins, genetic diversity and disease susceptibility. There is a clear scientific and public health need to develop large-scale projects that examine disease susceptibility across diverse populations across the continent. That work should be integrated with initiatives to improve research capacity in Africa.”

    The researchers hope this work will trigger larger and more diverse studies of genetic causes of disease across the region and the development of new treatments that will benefit both those living in Africa and people of African descent around the world. The study underscores the importance of having globally diverse participant cohorts in genetics research.

    Before this project, which was largely funded by the United Kingdom’s Medical Research Council and Wellcome, only a few hundred whole genome sequences of African people had been completed. Researchers largely relied on genetic data from African-Americans which does not reflect the continent’s full diversity.

    The data was collected by researchers from universities and research institutes from Africa and the UK, led by Queen Mary University of London and including the University of KwaZuluNatal, MRC/UVRI & London School of Hygiene & Tropical Medicine Uganda Research Unit, the US National Institute of Health and the University of Cambridge.

    Important gene variants found in certain African populations
    EurekAlert! (31-OCT-2019):
     
    In the nearly 20 years since the Human Genome Project was completed, experts in genetic variants increasingly have raised concerns about the overemphasis on studying people of European descent when performing large population studies. A study appearing October 31 in the journal Cell aims to address some of this disparity by focusing on populations living in rural Uganda, thus revealing several new genetic variants related to human health.

    "This study highlights the high level of diversity in African populations that remains undiscovered despite large numbers of gene sequences that have been generated from Europeans," says co-senior author Manjinder Sandhu, who studies genomic diversity at the University of Cambridge in the UK. "We found that more than a quarter of the genetic variation we observed in the Ugandan population had not been discovered."

    The participants in the study came from 25 villages in a rural part of southwestern Uganda. Using blood samples, the investigators generated genotypes from about 5,000 individuals and conducted whole-genome sequencing on about 2,000 individuals. The researchers collected information through electronic questionnaires; carried out physical measurements such as blood pressure, height, and weight; and tested the blood samples for medically important markers such as cholesterol and glucose.

    The investigators made several findings related to genetic variants and health. "We found many new associations with blood traits, liver function tests, and glucose-related traits," Sandhu says. "Most of these relate to genetic variants that are either unique to Africans or rare in non-Africans. They may not have been readily discovered even in very large studies of non-African populations."

    Specifically, they found that height is less genetically determined among rural Ugandans relative to what's been seen in European studies. In contrast, LDL cholesterol levels appear to be more genetically determined relative to Europeans.

    "We think this might relate to differences in the impact of diet and nutrition relative to genetic influences between African and European populations," says co-first author Deepti Gurdasani, a career development fellow at Queen Mary's University of London. "For example, the genetic influences on height might be more limited by malnutrition in early childhood in these populations. On the other hand, so-called Western dietary patterns possibly have a lower influence on cholesterol levels, making these more genetically determined."

    The researchers also found an association between a genetic variant that causes alpha-thalassemia among Africans and levels of glycated hemoglobin. This genetic variant, found in 22% of Africans, protects against severe malaria. It is rare in populations where malaria isn't endemic. "Because glycated hemoglobin is commonly used to diagnose diabetes, this finding suggests that it needs careful evaluation as a test for diabetes in relevant populations," says co-senior author Ayesha Motala, of KwaZulu Natal University in South Africa.

    The study also revealed important findings about human history and migration. "Uganda is a melting pot of different cultures and languages, and we wanted to understand the genetic structure and history of populations within the country,"says Pontiano Kaleebu, the Director of Uganda Virus Research Institute and Director of the MRC/UVRI & London School of Hygiene and Tropical Medicine Uganda Research Unit, who co-led the project. [B]"These studies highlight the extensive movement and population expansions that have occurred within and into Africa over the past few thousand years."

    Analysis revealed that the genomes of Ugandans are a mosaic of many ancestries, likely reflecting the extensive migration from surrounding regions spanning hundreds to thousands of years. It also showed that significant Eurasian ancestry has entered the region at multiple time points, ranging from a few hundred years ago to about 4,000 years ago.

    Although the researchers identified new genetic variants associated with disease, they say much more research is needed to understand how these genetic variants affect disease traits. This will require not just looking at genomes but also at functional effects of genomes on gene expression and protein levels.

    In the future, they also plan to look at individuals from other parts of Africa, especially indigenous hunter-gatherer populations such as the Khoe-San populations in Namibia and South Africa and the rainforest hunter-gatherer populations in central Africa.

    "This study confirms that genetic causes of disease may be different in Africans and provides opportunities to identify new genes associated with disease that would not be identified in European studies," Gurdasani concludes. "This kind of research will allow us to identify new targets for therapies that could potentially be useful for all populations."

    ###

    This work was funded by the Wellcome Trust, the Wellcome Sanger Institute, the UK Medical Research Council, and the Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine Uganda Research Unit core funding. This work was funded in part by IAVI with the generous support of the United States Agency for International Development and other donors.

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    "...the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals "
    For a paper of this magnitude, I found the takeaways disturbingly underwhelming from a strictly ancestral standpoint:

    • mtDNA and Y-DNA only shown at the highest macro-level (Fig S4) -- there's been Ugandan papers as far back as a ~decade ago with better hg definition (Isabirye, ‎2010), (Gomes, 2015)
    • Outdated citations consistently stated throughout the paper from a 1954 reference!?
    • A lot of incorrect terminology used for an academic paper (Tanganyika mentioned as a "district"... district of what?!). West-Nile Ugandans grouped as to "...often speak Nilotic languages" even though this region is predominately Central-Sudanic (completely different branch of the Nilo-Saharan linguistic family)
    • Inaccessible samples -- the paper would've been better pardoned if the samples were at least left public for open analysis (G25 nMonte, ADMIXTURE...).
    • Limited to no representation of Northern and Eastern Ugandans; Nilo-Saharan speakers which populate nearly half the country's landmass are only vaguely mentioned as "Other" when sampled
    • Probably the most meaningful PCA (Fig S2 E) has an unintelligible legend
    • Too many ethnic groups are disproportionately surveyed for quick glance comparison; the disarray is shown when groups are tallied on the PCA and ADMIXTURE runs (impossible to make out Batoro/Basoga/Dinka on K runs)
    • Somehow Batanzania, which actually isn't an ethnic group, are represented over staple Ugandan pops (Lango, Teso..) -- this would be equivalent to having the largest U.K. paper, ignoring the Scots and Welsh but surveying locals of French decent


    - hoping more value was met on the bio-medical front (traits, African specific-variants...etc)

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    Finally!!!!!
    This is beautiful guys. The melting pot of all African major groups is being studied on both ancestry and health.
    I hope commercial companies use these whole genome data to improve their results. It’s not ideal how they can use African-Americans and/or Eurasians to look for a gene associated with a certain disease or trait in native east/South Africans .
    According to 23andme, I have straight to curly hair. Lol. They got be kidding me

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    Quote Originally Posted by Espoir View Post
    Finally!!!!!
    This is beautiful guys. The melting pot of all African major groups is being studied on both ancestry and health.
    I hope commercial companies use these whole genome data to improve their results. It’s not ideal how they can use African-Americans and/or Eurasians to look for a gene associated with a certain disease or trait in native east/South Africans .
    According to 23andme, I have straight to curly hair. Lol. They got be kidding me
    Issue is even if they use Africans for health traits is that it won't apply to all Africans as well due to more genetic diversity vs Europe/West Eurasia. For example, I carry this lactase persistence SNP that peaks in the Afar. Doubtful it would say much about lactase persistence in other Africans like that European version they have on 23andMe.

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    Quote Originally Posted by NetNomad View Post
    Issue is even if they use Africans for health traits is that it won't apply to all Africans as well due to more genetic diversity vs Europe/West Eurasia. For example, I carry this lactase persistence SNP that peaks in the Afar. Doubtful it would say much about lactase persistence in other Africans like that European version they have on 23andMe.
    I concur.
    It’s unfair to anyone paying money for health services and don’t get accurate results.
    I guess Tishkoff study that was done on East Africans can add great value to their products, hence benefit East Africans in general( HGs, Afroasiatic and NiloSaharan).
    This study is also gonna help coz, it incorporates Niger-Congo, NiloSaharan and those groups with affinities to Afroasiatic populations

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    According to another article, the Sanger Institute guys bought 75 000 African genetics chips from ThermoFisher which are now going to waste because they didn't have permission to give them all the data. Yeesh.

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