Population genetics models of local ancestry

Migrations have played an important role in shaping the genetic diversity of human populations. Understanding genomic data thus requires careful modeling of historical gene flow. Here we consider the effect of relatively recent population structure and gene flow, and interpret genomes of individuals that have ancestry from multiple source populations as mosaics of segments originating from each population. We propose general and tractable models for describing the evolution of these patterns of local ancestry and their impact on genetic diversity. We focus on the length distribution of continuous ancestry tracts, and the variance in total ancestry proportions among individuals. The proposed models offer improved agreement with Wright-Fisher simulation data when compared to state-of-the art models, and can be used to infer various demographic parameters in gene flow models. Considering HapMap African-American (ASW) data, we find that a model with two distinct phases of `European' gene flow significantly improves the modeling of both tract lengths and ancestry variances.Comment: 25 pages with 7 figures; Genetics: Published online before print April 4, 201

Mapping genes underlying ethnic differences in tuberculosis risk by linkage disequilibrium in the South African coloured population of the Western Cape

Includes bibliographical references.The South Africa Coloured population of the Western Cape is the result of unions between Europeans, Africans (Bantu and Khoisan), and various other populations (Malaysian or Indonesian descent). The world-wide burden of tuberculosis remains an enormous problem, and is particularly severe in this population. In general, admixed populations that have arisen in historical times can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Despite numerous successful genome-wide association studies, detecting variants that have low disease risk still poses a challenge. Furthermore, admixture association studies for multi-way admixed populations pose constant challenges, including the choice of an accurate ancestral panel to infer ancestry and for imputing missing genotypes to identify possible genetic variants causing susceptibility to disease. This thesis addresses some of these challenges. We first developed PROXYANC, an approach to select the best proxy ancestral populations for admixed populations. From the simulation of a multi-way admixed population, we demonstrated the ability and accuracy of PROXYANC in selecting the best proxy ancestry and illustrated the importance of the choice of ancestries in both estimating admixture proportions and imputing missing genotypes. We applied this approach to the South African Coloured population, to refine both the choice of ancestral populations and their genetic contributions. We also demonstrated that the ancestral allele frequency differences correlated with increased linkage disequilibrium in the SAC, and that the increased LD originates from admixture events rather than population bottlenecks. Secondly, we conducted a study to determine whether ancestry-specific genetic contributions affect tuberculosis risk. We additionally conducted imputation genome-wide association studies and a meta-analysis incorporating previous genome-wide association studies of tuberculosis

Sensitive Detection of Chromosomal Segments of Distinct Ancestry in Admixed Populations

Identifying the ancestry of chromosomal segments of distinct ancestry has a wide range of applications from disease mapping to learning about history. Most methods require the use of unlinked markers; but, using all markers from genome-wide scanning arrays, it should in principle be possible to infer the ancestry of even very small segments with exquisite accuracy. We describe a method, HAPMIX, which employs an explicit population genetic model to perform such local ancestry inference based on fine-scale variation data. We show that HAPMIX outperforms other methods, and we explore its utility for inferring ancestry, learning about ancestral populations, and inferring dates of admixture. We validate the method empirically by applying it to populations that have experienced recent and ancient admixture: 935 African Americans from the United States and 29 Mozabites from North Africa. HAPMIX will be of particular utility for mapping disease genes in recently admixed populations, as its accurate estimates of local ancestry permit admixture and case-control association signals to be combined, enabling more powerful tests of association than with either signal alone

Fast and efficient statistical methods for detecting genetic admixture events and its applications in large-scale data cohorts

Present-day cohorts of genome-wide DNA provide a powerful means of elucidating admixture events where different human groups intermixed, providing new insights into human history and population movements. The method GLOBETROTTER (Hellenthal et al., 2014) shows increased precision over other available techniques for characterising admixture due to modelling haplotype information, i.e. associations among tightly linked Single Nucleotide Polymorphisms (SNPs). However, because of its computational demands, GLOBETROTTER can only handle relatively small sample sizes of tens to hundreds of admixed individuals. In this thesis, I present a new statistical method, fastGLOBETROTTER, that both reduces computational time and increases accuracy relative to GLOBETROTTER. In particular, fastGLOBETROTTER more efficiently models admixture linkage disequilibrium by sampling sets of genomic regions within individuals that are the most informative for admixture events. Additionally, I have developed an algorithm for allocating memory more efficiently to enable a factor of up to 20 fold improvement in computation time relative to GLOBETROTTER. Therefore, this technique can cope with the rapidly emerging large-scale cohorts of genetically homogeneous populations sampled from small geographic regions, e.g. within a country (China Kadoorie Biobank, UK Biobank), to provide more precise estimates of admixture dates. Via simulations, I use fastGLOBETROTTER to demonstrate the sample sizes required to characterize admixture between groups with high levels of genetic similarity, and the time depths for which these approaches can reliably detect such past intermixing. I also apply fastGLOBETROTTER to over 6000 European individuals, using over 2500 individuals as ancestry surrogates, revealing new insights into admixture across Western Europe. These include admixture events dated to ∼500-600 CE from sources carrying DNA related to present-day West Asian and North African populations found in individuals within France, Belgium and parts of Germany. I also report admixture from East-Asian/Siberian-like sources in individuals within Finland, Norway and Sweden at different times starting ∼1900 years ago

Enhancements to the ADMIXTURE algorithm for individual ancestry estimation

<p>Abstract</p> <p>Background</p> <p>The estimation of individual ancestry from genetic data has become essential to applied population genetics and genetic epidemiology. Software programs for calculating ancestry estimates have become essential tools in the geneticist's analytic arsenal.</p> <p>Results</p> <p>Here we describe four enhancements to ADMIXTURE, a high-performance tool for estimating individual ancestries and population allele frequencies from SNP (single nucleotide polymorphism) data. First, ADMIXTURE can be used to estimate the number of underlying populations through cross-validation. Second, individuals of known ancestry can be exploited in supervised learning to yield more precise ancestry estimates. Third, by penalizing small admixture coefficients for each individual, one can encourage model parsimony, often yielding more interpretable results for small datasets or datasets with large numbers of ancestral populations. Finally, by exploiting multiple processors, large datasets can be analyzed even more rapidly.</p> <p>Conclusions</p> <p>The enhancements we have described make ADMIXTURE a more accurate, efficient, and versatile tool for ancestry estimation.</p

Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities

This review explores the limitations of self-reported race, ethnicity, and genetic ancestry in biomedical research. Various terminologies are used to classify human differences in genomic research including race, ethnicity, and ancestry. Although race and ethnicity are related, race refers to a person’s physical appearance, such as skin color and eye color. Ethnicity, on the other hand, refers to communality in cultural heritage, language, social practice, traditions, and geopolitical factors. Genetic ancestry inferred using ancestry informative markers (AIMs) is based on genetic/genomic data. Phenotype-based race/ethnicity information and data computed using AIMs often disagree. For example, self-reporting African Americans can have drastically different levels of African or European ancestry. Genetic analysis of individual ancestry shows that some self-identified African Americans have up to 99% of European ancestry, whereas some self-identified European Americans have substantial admixture from African ancestry. Similarly, African ancestry in the Latino population varies between 3% in Mexican Americans to 16% in Puerto Ricans. The implication of this is that, in African American or Latino populations, self-reported ancestry may not be as accurate as direct assessment of individual genomic information in predicting treatment outcomes. To better understand human genetic variation in the context of health disparities, we suggest using “ancestry” (or biogeographical ancestry) to describe actual genetic variation, “race” to describe health disparity in societies characterized by racial categories, and “ethnicity” to describe traditions, lifestyle, diet, and values. We also suggest using ancestry informative markers for precise characterization of individuals’ biological ancestry. Understanding the sources of human genetic variation and the causes of health disparities could lead to interventions that would improve the health of all individuals

Ameerika populatsioonide genoomne portree

Väitekirja elektrooniline versioon ei sisalda publikatsiooneAmeerika populatsioonide evolutsiooni on käsitlenud mitmed multidistsiplinaarsed uuringud. Meie teadmised Ameerika maailmajao geneetilise mitmekesisuse kujunemisest on endiselt ebatäielikud, ehkki geneetilised uuringud lisavad sel teemal pidevalt uusi detaile. Uute tehnoloogiate nagu järgmise põlvkonna sekveneerimine (NGS) väljaarendamine koos teiste tehniliste edasiminekutega avavad võimaluse eraldada ja analüüsida DNA-d iidsetest proovidest, tehes "iidsest genoomikast" (aDNA) ühe paljudest põhilistest tööriistadest meie esivanemate mineviku mõistmiseks. Veelgi enam, need tehnoloogiad on tohutult suurendanud genoomsete andmete hulka kogu maailmast, sealhulgas Ameerika mandritelt. Ehkki Ameerika maailmajagu oli viimane, milleni meie sapiens’i esivanemad jõudsid, on selle geneetilise varieeruvuse protsessid olnud väga keerukad. Nende uuringud on rohkem kui kolme kümnendi jooksul olnud paljude geneetikaalaste teadustööde teemaks. Algul domineerisid Ameerika populatsioonide populatsioonigeneetilistes uuringutes uniparentaalsed geneetilised süsteemid, alustades mitokondriaalse DNA-ga (mtDNA) ja peagi kaasates Y-kromosoomi (chrY) analüüsi. Viimasest selgus, et põlisameeriklaste kaks chrY asutajahaplogruppi olid tõenäoliselt hg C ja hg Q, mida leiti vastavalt umbes 5% ja 75% põlisameerika meestest. Kuid nende haplogruppide resolutsioon ei paranenud oluliselt enne kui mõne aasta eest. Selle doktoritöö esimese publikatsiooni (Ref I) eesmärgiks on uurida Ameerika maailmajao geneetilist ajalugu meeste perspektiivist, lahates suure täpsusastmega üleameerikalist haplogruppi Q, ning koostada kõikehõlmav ja detailne haplogrupp Q ja selle alamliinide fülogeograafia. Uniparentaalseid geneetilisi süsteeme võib pidada kaheks lookuseks, mida kasutatakse inimese ajaloo nais- ja meesperspektiivi mõistmiseks. Nad saavad kirjeldada ainult kaht esivanemat neist tuhandetest, kes on seotud tänapäeva populatsioonide geneetilise pärandi kujundamisega. Olulisem arv esivanemaid on genoomis esindatud autosomaalsetes markerites. Seega on autosomaalsed markerid hädavajalikud Ameerika maailmajao populatsioonide liikumiste ajastuse ja dünaamika mõistmiseks. Tänu arheoloogilistele ja geneetilistele tõenditele tunnistatakse nüüdseks, et esimesed Põhja-Ameerikasse jõudnud inimesed tulid Siberist, ületades pärast hilist jääaega Beringi maakitsuse. Algsetele asulakohtadele järgnesid ulatuslikud inimeste ränded, mis jõudsid Lõuna-Ameerika lõunaossa suhteliselt kiiresti, juba ~15 000 aastat tagasi. Mitu hiljutist uuringut on selle teema kohta uut informatsiooni andnud, rekonstrueerides Ameerika maailmajao erinevate piirkondade põliselanike rühmade genoomset ajalugu, kuid Isthmo-Colombia piirkond on seni puudu. Seega rakendab selle doktoritöö teine publikatsioon (Ref II) nii iidse kui ka tänapäeva DNA andmete analüüsi, et rekonstrueerida Isthmo-Colombia piirkonna genoomset ajalugu. Selle eesmärgiks on teha kindlaks Panama põlispopulatsioonide genoomne taust, et hinnata maakitsuse sisest varieeruvust ja selgitada Kolumbuse-eelsete ameeriklaste genoomset ajalugu, hinnates Isthmo-Colombia piirkonna sidemeid ülejäänud Ameerika maailmajaoga. Lisaks esialgsetele rännetele pärinevad Ameerika populatsioonid mitmest segunemisest, alates koloniseerimisest ja Atlandi orjakaubandusest. Peale selle toimus viimase kahe sajandi jooksul palju rändelaineid, millele järgnes kohalik segunemine, ning nende mõju on suuresti uurimata. Selle doktoritöö kolmas publikatsioon (Ref III) uurib, kuidas hilisemad ränded kujundasid segunenud Ameerika populatsioonide genoomset tausta. Täpsemalt on selle uuringu eesmärgiks rekonstrueerida kõrgel lahutusastmel põlvnemise komponendid, anda hinnang segunemise ajale, uurida erinevate mandrite põlvnemise demograafilist evolutsiooni pärast segunemist ning hinnata soost sõltuva geenivoolu dünaamika ulatust ja tugevust segunenud Ameerika populatsioonides. Käesoleva doktoritöö peamised tulemused ja järeldused on järgmised: • Tehti kindlaks ja dateeriti kõrge resolutsiooniga haplogrupp Q fülogeneesipuu, mis annab uut informatsiooni oma Euraasia ja Ameerika harude geograafilise jaotuse kohta tänapäeva ja iidsetes proovides. • Esimest korda tuvastati kaks eristuvat Y-kromosoomi liini, mis peegeldavad hiljutistes genoomsetes uuringutes varem kirjeldatud kaht peamist põlvnemiskomponenti (SNA ja NNA). Nende liinide lahknemine toimus tõenäoliselt Beringi maakitsuse idaosas enne Ameerika maailmajakku sisenemist, milleks kasutati kaht teed: ranniku (SNA, Q-Z780/Q-M848) ja sisemaa teed (NNA, Q-Y4276). Sinna jõudnuna segunesid need kaks põlvnemiskomponenti Põhja-Ameerikas tõenäoliselt väga vara, millele viitab iidne Kennewicki mees, kelle tuumagenoom kuulub SNA komponenti (Q-M848), kuid mtDNA haplogrupp on NNA-st (X2a). • Avastati SNA liinide kaks märkimisväärset ekspansiooni Meso- ja Lõuna-Ameerikas, üks umbes 15 000 aastat tagasi, kohe pärast esmaasustamist, ja teine 3000 aastat tagasi pärast klimaatilisi muutusi ja kohalikke kultuurilisi nihkeid. • Panama sees tuvastati märkimisväärne geneetiline struktuur, mis kattus üldjoontes käesolevas uuringus analüüsitud mineviku ja praeguste põliselanike rühmadega. Need rühmad on ka tuhandeid aastaid suguluses olnud, eriti Kariibi mere piirkonnas Panama lääne- ja Costa Rica kaguosa piiril. Ida-Panama põliselanike rühmade vahel ning Emberá ja hispaanlaste-eelsete panamalaste vahel, kes elasid Vana Panamat ümbritsevas piirkonnas enne kontakti eurooplastega, leiti vähem geneetilisi sarnasusi. • Ameerika maailmajao iidsete põliselanike seas avastati varem kirjeldamata põlvnemiskomponent. See komponent esineb ainult selles piirkonnas ning on tuvastatav iidsetes hispaanlaste-eelsetes indiviidides ja inimestes, kes ise identifitseerivad end tänapäeva põliselanike, Aafrika ja latiino-põliselanike rühmade järglastena. See jõudis Panama maakitsusele rohkem kui 10 000 aastat tagasi, levis varases Holotseenis lokaalselt ning jättis tänapäevani püsivaid genoomseid jälgi, eriti Guna rahva hulgas. • Euroopa geneetiline panus Ameerika populatsioonidesse peegeldab kolonisatsiooni aegset geopoliitilist olukorda. Avastati mitu sekundaarset Euroopa allikat, mis panustasid arvestatavasse osassse Ameerika populatsioonidest, nt Itaalia Brasiilias ja Argentiinas, Kesk-Euroopa Brasiilias. Tuletati Aafrika allikate eristuv panus Ameerika populatsioonidesse. • Segunemise ajad langevad kokku rändelainetega Euroopast ja peegeldavad ekspluateeritud Aafrika piirkondade muutumist ajas. • Segunemise demograafilise mõju analüüsist selgub üldine languse ja taastumise muster mitmes uuritavas populatsioonis, mis vastab koloniaalajastu algusele ja lõpule. Kuid Peruud ja Mehhikot iseloomustavad erinevad demograafilised trajektoorid. • Soost sõltuva segunemise dünaamika analüüs viitab sellele, et tänapäeva populatsioonidesse on panustanud rohkem Ameerika naisi kui mehi. Vastupidiselt oli Euroopa meeste panus olulisem kui samalt mandrilt pärinevate naiste oma. Sellele vastandlikult ilmnes mõnes populatsioonis, kuid mitte kõigis, tõendeid suuremast naiste panusest, mis on osaliselt vastuolus ajalooliste andmetega Aafrika päritolust.The evolution of American populations has been the subject of several multidisciplinary studies. Our knowledge regarding the formation of the genetic diversity of the Americas is still incomplete, although genetic studies are constantly adding new details on this topic. The development of new technologies, such as Next Generation Sequencing (NGS), together with other technical improvements, lead to the possibility of extracting and analysing DNA from ancient specimens, making "ancient genomic" (aDNA) one of the many fundamental tools to understand our ancestor's past. Moreover, these technologies enormously increased the number of worldwide genomic data, including those from the Americas. Although the Americas were the last continents to be reached by our sapiens ancestors, their genetic variation processes have been extremely complex. Their studies have been the topic of many genetic surveys for more than three decades. In the beginning, uniparental systems dominated the population genetics research of American populations. It started with mitochondrial DNA (mtDNA) and soon included the Y chromosome (chrY) analysis. The latter revealed that the two founding Native American chrY haplogroups probably were Hg C and Hg Q, accounting for about 5% and 75% of Native American males, respectively. However, the resolution of these haplogroups did not undergo substantial improvements until a few years ago. The first publication included in this dissertation (Ref I) aims to investigate from a male perspective the genetic history of the Americas through a fine dissection of the Pan-American haplogroup Q and to reconstruct a comprehensive and detailed haplogroup Q phylogeography and that of its sub-lineages. The uniparental systems could be considered as two loci that are used to understand the female and male perspective of human history. They can describe only two ancestors of the thousands involved in shaping the genetic legacy of modern populations. The genomic representation of a more significant number of ancestors is encrypted in the autosomal markers. Therefore, autosomal markers are crucial to understanding the timing and the dynamics of population movements in the Americas. Thanks to archaeological and genetic evidence, it is now accepted that the first people arriving in North America came from Siberia, passing through Beringia after late Glacial times. Initial settlements were followed by widespread people movements that reached southern South America relatively fast, as early as ~15 thousand years ago. Several recent studies have provided new information about this subject, reconstructing the genomic history of indigenous groups from different regions of the Americas, but the Isthmo-Colombian area is still lacking. Hence, the second publication of this thesis (Ref II) employed both ancient and modern DNA data analysis to reconstruct the genomic history of the Isthmo-Colombian area. It aims to define the genomic background of Panamanian indigenous populations to evaluate the intra-Isthmus variability and shed light on pre-Columbian Americans' genomic history assessing the connection between the Isthmo-Colombian area and the rest of the Americas. Besides the first migrations, American populations result from several admixture events since the colonial era and the Atlantic slave trade. Moreover, many waves of migration followed by local admixture occurred in the last two centuries, the impact of which has been largely unexplored. The third reference in this thesis (Ref III) explores how more recent migrations shaped the genomic background of admixed American populations. In particular, this study aims to reconstruct the fine-scale ancestry composition, estimate the time of admixture, examine the demographic evolution of different continental ancestries after the admixture and assess the extent and magnitude of sex-biased gene-flow dynamics in admixed American populations. The main results and conclusions of this research thesis are the following: • A high-resolution haplogroup Q phylogeny that presents new insights into its Eurasian and American branches' geographic distribution in modern and ancient samples was ascertained and dated. • For the first time, two distinct Y chromosome lineages reflecting the two main ancestral components (SNA and NNA) earlier described by recent genomic studies were observed. The differentiation of these lineages probably occurred in eastern Beringia before entering the Americas through two routes: the coastal (SNA, Q-Z780/Q-M848) and the internal route (NNA, Q-Y4276). Once there, these two ancestral components probably admixed very early in North America, as suggested by the ancient Kennewick nuclear genome belonging to SNA (Q-M848) yet carrying an NNA mtDNA haplogroup (X2a). • Two significant expansions of the SNA lineages in Meso- and South America, one around 15 kya, early after the first peopling, and another at 3 kya, following climatic changes and local cultural shifts, were revealed. • A remarkable genomic structure within Panama was identified, mainly overlapping with past and present Indigenous groups analysed in this study. These groups also show relatedness, especially in the Caribbean region on the border between western Panama and southeastern Costa Rica over thousands of years. Fewer genetic similarities were identified between the Indigenous groups located in eastern Panama and between the Emberá and the pre-Hispanic Panamanians who lived in the area around Old Panama before European contact. • A previously undescribed ancestry among ancient Indigenous peoples of the Americas was revealed. This ancestry is unique to the region and detectable in the ancient pre-Hispanic individuals and the self-identified descendants of current Indigenous, African and Hispano-Indigenous groups. It reached the Panama land bridge over 10 thousand years ago, expanded locally during the early Holocene, and left genomic traces up to the present day, especially among the Guna. • The European genetic contribution in American populations mirrors the geopolitical situation during colonisation. Several European secondary sources contributing to a substantial proportion of American populations were revealed, e.g. Italy in Brazil and Argentina, Central Europe in Brazil. A differential contribution of African sources among American populations was inferred. • Times of admixture are concordant with migration waves from Europe and reflect differences in African areas exploited through time. • The investigation of the demographic impact of admixture reveals a general decline and recovery pattern in several populations under study corresponding to the beginning and the end of the Colonial Era. However, Peru and Mexico are characterised by different demographic trajectories. • The analysis of sex-biased admixture dynamics suggests that a higher number of American females than males have contributed to the modern populations. In contrast, European males had a more significant contribution than females from the same continent. In contrast, some populations, but not all, showed evidence for a higher female contribution, partially conflicting with historical records for African ancestry.https://www.ester.ee/record=b545015

Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities

This review explores the limitations of self-reported race, ethnicity, and genetic ancestry in biomedical research. Various terminologies are used to classify human differences in genomic research including race, ethnicity, and ancestry. Although race and ethnicity are related, race refers to a person’s physical appearance, such as skin color and eye color. Ethnicity, on the other hand, refers to communality in cultural heritage, language, social practice, traditions, and geopolitical factors. Genetic ancestry inferred using ancestry informative markers (AIMs) is based on genetic/genomic data. Phenotype-based race/ethnicity information and data computed using AIMs often disagree. For example, self-reporting African Americans can have drastically different levels of African or European ancestry. Genetic analysis of individual ancestry shows that some self-identified African Americans have up to 99% of European ancestry, whereas some self-identified European Americans have substantial admixture from African ancestry. Similarly, African ancestry in the Latino population varies between 3% in Mexican Americans to 16% in Puerto Ricans. The implication of this is that, in African American or Latino populations, self-reported ancestry may not be as accurate as direct assessment of individual genomic information in predicting treatment outcomes. To better understand human genetic variation in the context of health disparities, we suggest using “ancestry” (or biogeographical ancestry) to describe actual genetic variation, “race” to describe health disparity in societies characterized by racial categories, and “ethnicity” to describe traditions, lifestyle, diet, and values. We also suggest using ancestry informative markers for precise characterization of individuals’ biological ancestry. Understanding the sources of human genetic variation and the causes of health disparities could lead to interventions that would improve the health of all individuals