DOCSLIB.ORG

Haplotypes and Linkage Disequilibrium at the Phenylalanine Hydroxylase Locus, PAH, in a Global Representation of Populations Judith R

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Haplotypes and Linkage Disequilibrium at the Phenylalanine Hydroxylase Locus, PAH, in a Global Representation of Populations Judith R Am. J. Hum. Genet. 66:1882±1899, 2000 Haplotypes and Linkage Disequilibrium at the Phenylalanine Hydroxylase Locus, PAH, in a Global Representation of Populations Judith R. Kidd,1 Andrew J. Pakstis,1 Hongyu Zhao,2 Ru-Band Lu,4 Friday E. Okonofua,5 Adekunle Odunsi,6 Elena Grigorenko,3, Batsheva Bonne-Tamir,7 Jonathan Friedlaender,8 Leslie O. Schulz,9 Josef Parnas,10 and Kenneth K. Kidd1 Departments of 1Genetics, 2Epidemiology and Public Health, and 3Psychology and Child Study Center, Yale University, New Haven, CT; 4Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 5University of Benin, Faculty of Medicine, Benin City, Nigeria; 6Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo; 7Department of Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv; 8Department of Anthropology, Temple University, Philadelphia; 9Department of Health Sciences, University of Wisconsin, Milwaukee; and 10Institute of Preventative Medicine, Kommune Hospitalet, Copenhagen Because defects in the phenylalanine hydroxylase gene (PAH) cause phenylketonuria (PKU), PAH was studied for normal polymorphisms and linkage disequilibrium soon after the gene was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed that haplotype-frequency variation exists between some regions of the world. In European populations, linkage disequilibrium generally was found not to exist between RFLPs at opposite ends of the gene but was found to exist among the RFLPs clustered at each end. We have now undertaken the ®rst global survey of normal variation and disequilibrium across the PAH gene. Four well-mapped single-nucleotide polymorphisms (SNPs) spanning »75 kb, two near each end of the gene, were selected to allow linkage disequilibrium across most of the gene to be examined. These SNPs were studied as PCR-RFLP markers in samples of, on average, 50 individuals for each of 29 populations, including, for the ®rst time, multiple populations from Africa and from the Americas. All four sites are polymorphic in all 29 populations. Although all but 5 of the 16 possible haplotypes reach frequencies 15% somewhere in the world, no haplotype was seen in all populations. Overall linkage disequilibrium is highly signi®cant in all populations, but disequilibrium between the opposite ends is signi®cant only in Native American populations and in one African population. This study demonstrates that the physical extent of linkage disequilibrium can differ substantially among populations from different regions of the world, because of both ancient genetic drift in the ancestor common to a large regional group of modern populations and recent genetic drift affecting individual populations. Introduction (Kazazian et al. 1984), as well as studies at the phenyl- alanine hydroxylase locus (PAH) to identify phenyl- Linkage disequilibrium or, more generally, gametic- ketonuria (PKU [MIM 261600]) mutants (DiLella et al. phase allelic association, is the nonrandom occurrence 1986a, 1987). of alleles on chromosomes (i.e., in gametes) in a popu- PKU is one of the most common genetic diseases in lation. Linkage disequilibrium has become an important people of northern-European descent, occurring in that tool in the end stages of positional cloning because a group at an average rate of »1/10,000 live births (Bickel recently arisen single deleterious allele will usually be et al. 1981). The PAH gene, coding for the enzyme nonrandomly associated with the alleles at nearby poly- phenylalanine hydroxylase (PAH), was implicated as the morphic sites that were on the chromosome on which etiologic gene, by the absence of PAH enzyme activity the mutation originally occurred. Among the earliest ap- in patients with PKU (Friedman et al. 1973). The human plications of this principle for identi®cation of distinct PAH cDNA was cloned (Woo et al. 1983; Kwok et al. mutations associated with a disease were studies at the 1985), RFLPs were identi®ed by use of the cDNA as b-hemoglobin cluster to identify thalassemia mutants the probe (Woo et al. 1983; Lidsky et al. 1985a), the gene was mapped to human chromosome 12q22-24 (Lidsky et al. 1985b), and the molecular structure of Received December 23, 1999; accepted for publication March 14, 2000; electronically published April 27, 2000. the gene was described (DiLella et al. 1986a), relatively Address for correspondence and reprints: Dr. Judith R. Kidd, early in the history of recombinant-DNA studies. When Department of Genetics, SHM I353, Yale University School of Med- the RFLPs encompassing the gene were used, it was icine, 333 Cedar Street, New Haven, CT 06520-8005. E-mail: kidd obvious that PKU mutations occurred on several dif- @biomed.med.yale.edu q 2000 by The American Society of Human Genetics. All rights reserved. ferent haplotypes. By 1986 it was recognized that PKU 0002-9297/2000/6606-0017$02.00 was mutationally heterogeneous; at least some different 1882 Kidd et al.: A Global Survey of Disequilibrium at PAH 1883 PKU haplotypes were found to have different mutations ground haplotypes is maintained at the PAHdb Web site (DiLella et al. 1986b, 1987). Interestingly, in a sample (Nowacki et al. 1997). from Denmark, no signi®cant association could be dem- Studies of normal chromosomes in European popu- onstrated between the disease alleles and any single al- lations have shown that disequilibrium exists among the lele of the normal polymorphisms spanning the gene sites at either end of the gene, at distances of 22 and (Chakraborty et al. 1987). However, when haplotypes 31 kb, but, in general, either does not exist or is much of these polymorphisms were examined, two haplotypes weaker between markers located at opposite ends of the were signi®cantly more common among PKU chro- gene, at distances >43 kb (Chakraborty et al. 1987; mosomes than among normal chromosomes. The rea- Daiger et al. 1989a). A similar pattern has been ob- son for the absence of allelic association with individual served in a sample of 44 chromosomes from China and RFLPs was also obvious: the marker-allele frequencies Japan (Daiger et al. 1989b) and in a sample of 1600 among PKU chromosomes were very similar to the fre- chromosomes from several Polynesian groups (Hertz- quencies in normal chromosomes. In the case of normal berg et al. 1989). Other analyses of various published chromosomes, the two most common haplotypes were PAH data have reached similar conclusions (Feingold approximately equally frequent and had alternative al- et al. 1993; Degioanni and Darlu 1994). This pattern leles at most sites. The PKU chromosome(s) included of the molecular extent of linkage disequilibrium agrees those two haplotypes, but two others were the most with the ®ndings of Jorde et al. (1994)Ðthat linkage common, accounting for 20% and 38% of the PKU disequilibrium in populations of European origin gen- 1 chromosomes in the Danish sample; these two ªPKUº erally does not extend to 50±60 kb. Our recent studies haplotypes also had alternative alleles at all the sites at of linkage disequilibrium in multiple populations have which the two common normal haplotypes differed and found that linkage disequilibrium can differ dramati- had the same allele at all the sites at which the other cally among populations from different regions of the two were the same. This allelic complementarity of the world (Tishkoff et al. 1996a, 1996b, 1998; Kidd et al. most common haplotypes in both normal and PKU 1998). The only substantive reports of PAH haplotype chromosomes greatly reduced the power to detect allelic frequencies in speci®c non-European populationsÐ association of PKU with any single RFLP, although the Polynesians (Hertzberg et al. 1989) and eastern Asians (Daiger et al. 1989b)Ðshow reduced levels of hetero- association was obvious when haplotypes were used. zygosity relative to that in Europeans. The one small The two associated haplotypes were the basis for the study of African Americans (Hofman et al. 1991) has ®rst identi®cations of speci®c PKU mutations (DiLella found that haplotype frequencies for normal and PKU et al. 1986b, 1987). chromosomes differ from each other and from frequen- As the etiologically relevant mutations for PKU and cies in Europeans and Asians. the phenylalaninemia states became known, PAH hap- All of the previous studies of linkage disequilibrium lotypes of patients with PKU often signaled which mu- at the PAH locus have used pairwise coef®cients. The tation(s) a patient carried and/or alerted the researchers resulting matrix of disequilibrium coef®cients can show to the existence of previously unknown mutations a clear pattern but also often contains some pairwise (Daiger et al. 1989a, 1989b: Hertzberg et al. 1989; values that do not ®t into the general pattern of high Stuhrmann et al. 1989; Apold et al. 1990; Dianzani et absolute values for pairs of markers within either cluster al. 1990; Jaruzelska et al. 1991; Konecki and Lichter- and low absolute values for pairs of markers that bridge Konecki 1991; Svensson et al. 1991; Zygulska et al. the two clusters. As we have begun to consider linkage 1991; Baric et al. 1992; Kozak et al. 1995). Thus, by disequilibrium in more-complex genetic systems, we 1989, polymorphisms, mutations, and haplotypes of the have introduced a new coef®cient to measure overall PAH region had ®nally become well characterized in nonrandomness across the entire haplotype (Kidd et al. patients with PKU (Woo 1988; Nowacki et al. 1997). 1998; Zhao et al. 1999). The coef®cient estimate is By 1996, the PKU mutations and their haplotypes were based on the permuted data of the observed samples. being used to infer the natural histories both of the A variant of the permutation test for overall signi®cance mutations themselves and of the populations carrying allows us to test signi®cance of the disequilibrium across those mutations (Scriver et al.
Load more

Recommended publications
  • Linkage Disequilibrium in Human Ribosomal Genes: Implications for Multigene Family Evolution
    Copyright 0 1988 by the Genetics Societyof America Linkage Disequilibrium in Human Ribosomal Genes: Implications for Multigene Family Evolution Peter Seperack,*” Montgomery Slatkin+ and Norman Arnheim*.* *Department of Biochemistry and Program in Cellular andDevelopmental Biology, State University of New York, Stony Brook, New York I 1794, ?Department of Zoology, University of California, Berkeley, California 94720, and *Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-0371 Manuscript received January8, 1988 Revised copy accepted April 2 1, 1988 ABSTRACT Members of the rDNA multigene family withina species do not evolve independently,rather, they evolve together in a concerted fashion.Between species, however, each multigenefamily does evolve independently indicating that mechanisms exist whichwill amplify and fix new mutations bothwithin populations and within species. In order to evaluate the possible mechanisms by which mutation, amplification and fixation occurwe have determined thelevel of linkage disequilibrium betweentwo polymorphic sites in human ribosomal genes in five racial groups and among individuals within two of these groups.The marked linkage disequilibriumwe observe within individuals suggeststhat sister chromatid exchangesare much more important than homologousor nonhomologous recombination events in the concerted evolution of the rDNA family and further that recent models of molecular drive may not apply to the evolution of the rDNA multigene family. HE human ribosomal gene family is composed of ferences among individualsin the geneticcomposition T approximately 400 members which arear- of the multigene family because they create linkage ranged in small tandem clusters on five pairs of chro- disequilibrium among different members of familythe mosomes (for reviews, see LONG and DAWID1980; (OHTA1980a, b;NAGYLAKI and PETES1982; SLATKIN WILSON1982).
    [Show full text]
  • The Effects of Natural Selection on Linkage Disequilibrium and Relative Fitness in Experimental Populations of Drosophila Melanogaster
    THE EFFECTS OF NATURAL SELECTION ON LINKAGE DISEQUILIBRIUM AND RELATIVE FITNESS IN EXPERIMENTAL POPULATIONS OF DROSOPHILA MELANOGASTER GRACE BERT CANNON] Department of Zoology, Washington University, St. Louis, Missouri Received April 16, 1963 process of natural selection may be studied in laboratory populations in '?to ways. First, the genetic changes which occur during the course of micro- evolutionary change can be followed and, second, accompanying this, the size of the populations can be measured. CARSON(1961 ) considers the relative size of a population to be an important measure of relative population fitness when com- paring genetically different populations of the same species under uniform en- vironmental conditions over a period of time. In the present experiment, the experimental procedure of CARSONwas utilized to study the effects of selection on certain gene combinations and to measure the level of relative population fitness reached during the microevolutionary process. Experimental populations were constructed with certain oligogenes in low fre- quency and in certain associations in order to provide a situation likely to be changed by natural selection. Specifically, oligogenes on the third chromosome were allowed to recombine freely with the homologous Oregon chromosome so that three separate blocks could be selected for introduction into homozygous Oregon populations. The introduction contained all five of the oligogenes. At intervals samples were re- moved from the populations and testcrossed to determine whether selection had favored the coupling or repulsion phases of these blocks. In addition, the fitness of the populations was measured. This paper will show first the changes in frequency of the various gene combi- nations which occurred in the three experimental populations.
    [Show full text]
  • Fisher's Fundamental Theorem of Natural Selection Steven A
    TREE vol. 7, no. 3, March 1992 Fisher's Fundamental Theorem of Natural Selection Steven A. Frank and Montgomery Slatkin relationship to Adaptive Land- scapes. We focus on three ques- tions: What did Fisher really mean by the Fundamental Theorem? is Fishes Fundamental Theorem of natural though it were governed by the Fisher's interpretation of the Fun- selection is one of the most widely cited average condition of the species or damental Theorem useful? Why was theories in evolutionary biology. Yet it has inter-breeding group' (Ref. 3, p. 58). Fisher misinterpreted, even though been argued that the standard interpret- Fisher also pointed out that he stated on many occasions that he ation of the theorem is very different from average fitness, measured by the was not talking about the average what Fisher meant to say. What Fisher intrinsic (malthusian) rate of in- fitness of a population? really meant can be illustrated by look- crease of a species, must fluctuate ing in a new way at a recent model for about zero (Ref. 4, pp. 41-45). What did Fisher really mean? the evolution of clutch size. Why Fisher Otherwise, if a species' rate of The standard interpretation of was misunderstood depends, in part, on the increase were consistently positive, the Fundamental Theorem is that contrasting views of evolution promoted by it would soon overrun the world, or natural selection increases the Fisher and Wright. if a species' rate of increase were average fitness of a population at a consistently negative, it would rate equal to the genetic variance in R.A.
    [Show full text]
  • The Role of Linkage Disequilibrium in the Evolution of Premating Isolation
    Heredity (2009) 102, 51–56 & 2009 Macmillan Publishers Limited All rights reserved 0018-067X/09 $32.00 www.nature.com/hdy SHORT REVIEW The role of linkage disequilibrium in the evolution of premating isolation MR Servedio Department of Biology, University of North Carolina, Chapel Hill, NC, USA The suggestion that speciation may often occur, or be such factors: one-allele versus two-allele mechanisms of completed, in the presence of gene flow has long been premating isolation, and the form of selection against hybrids contentious, due to an appreciation of the challenges to as it relates to its effect on the pathway between post- maintaining population- or species-specific gene combina- zygotic and prezygotic isolation. The goal of this discussion tions when gene flow is occurring. Linkage disequilibrium is not to thoroughly review these factors, but instead to between loci involved in postzygotic and premating isolation concentrate on aspects and implications of these solutions must often be built and maintained as the source of these that are currently underemphasized in the speciation species-specific genotypes. Here, I discuss proposed solu- literature. tions to facilitate the establishment and maintenance of Heredity (2009) 102, 51–56; doi:10.1038/hdy.2008.98; this linkage disequilibrium. I concentrate primarily on two published online 24 September 2008 Keywords: gene flow; recombination; reinforcement; speciation; sympatric speciation Introduction on the build-up of linkage disequilibrium between genes involved in premating and postzygotic isolation. Here, I There has been a long-standing emphasis in speciation discuss solutions that have been proposed to ease the research on describing conditions that may facilitate the conditions for speciation with gene flow.
    [Show full text]
  • Linkage Disequilibrium and Its Expectation in Human Populations
    Linkage Disequilibrium and Its Expectation in Human Populations John A. Sved School of Biological Sciences, University of Sydney, Australia inkage disequilibrium (LD), the association in popu- By the time that the possibility of LD mapping was Llations between genes at linked loci, has achieved realized (e.g., Ikonen, 1990) the terminology of LD a high degree of prominence in recent years, primar- was well established. Currently the term is increas- ily because of its use in identifying and cloning genes ingly used, with many thousands of PubMed of medical importance. The field has recently been references and over 100 Wikipedia references. Note reviewed by Slatkin (2008). The present article is also the confusion with ‘lethal dose’, ‘learning disabili- largely devoted to a review of the theory of LD in ties’ and other terms in literature searches involving populations, including historical aspects. the LD acronym. The chance of any more appropriate Keywords: linkage disequilibrium, linked identity-by- terminology seems to have passed, even if a simple descent, LD mapping, composite D, Hapmap and suitable term could be suggested. ‘Allelic associa- tion’ would seem a desirable term (e.g., Morton et al., 2001) but for the fact that the genes involved are, by definition, non-allelic. Other authors have preferred to The Terminology of LD use the term ‘gametic phase disequilibrium’ (e.g., It has been clear for many years that LD is prevalent Falconer & Mackay, 1996; Denniston, 2000) to take across much of the human genome (e.g., Conrad account of the possibility of LD between genes on dif- 2006), and presumably any other organism when it is ferent, a situation that can arise when many unlinked looked for (e.g., Farnir et al., 2000, in cattle).
    [Show full text]
  • Prediction of Identity by Descent Probabilities from Marker-Haplotypes Theo Meuwissen, Mike Goddard
    Prediction of identity by descent probabilities from marker-haplotypes Theo Meuwissen, Mike Goddard To cite this version: Theo Meuwissen, Mike Goddard. Prediction of identity by descent probabilities from marker-haplotypes. Genetics Selection Evolution, BioMed Central, 2001, 33 (6), pp.605-634. 10.1051/gse:2001134. hal-00894392 HAL Id: hal-00894392 https://hal.archives-ouvertes.fr/hal-00894392 Submitted on 1 Jan 2001 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Genet. Sel. Evol. 33 (2001) 605–634 605 © INRA, EDP Sciences, 2001 Original article Prediction of identity by descent probabilities from marker-haplotypes a; b Theo H.E. MEUWISSEN ∗, Mike E. GODDARD a Research Institute of Animal Science and Health, Box 65, 8200 AB Lelystad, The Netherlands b Institute of Land and Food Resources, University of Melbourne, Parkville Victorian Institute of Animal Science, Attwood, Victoria, Australia (Received 13 February 2001; accepted 11 June 2001) Abstract – The prediction of identity by descent (IBD) probabilities is essential for all methods that map quantitative trait loci (QTL). The IBD probabilities may be predicted from marker genotypes and/or pedigree information. Here, a method is presented that predicts IBD prob- abilities at a given chromosomal location given data on a haplotype of markers spanning that position.
    [Show full text]
  • Evolution at Multiple Loci
    Evolution at multiple loci • Linkage • Sex • Quantitative genetics Linkage • Linkage can be physical or statistical, we focus on physical - easier to understand • Because of recombination, Mendel develops law of independent assortment • But loci do not always assort independently, suppose they are close together on the same chromosome Haplotype - multilocus genotype • Contraction of ‘haploid-genotype’ – The genotype of a chromosome (gamete) • E.g. with two genes A and B with alleles A and a, and B and b • Possible haplotypes – AB; Ab; aB, ab • Will selection at the A locus affect evolution of the B locus? Chromosome (haplotype) frequency v. allele frequency • Example, suppose two populations have: – A allele frequency = 0.6, a allele frequency 0.4 – B allele frequency = 0.8, b allele frequency 0.2 • Are those populations identical? • Not always! Linkage (dis)equilibrium • Loci are in equilibrium if: – Proportion of B alleles found with A alleles is the same as b alleles found with A alleles; and • Loci in linkage disequilibrium if an allele at one locus is more likely to be found with a particular allele at another locus – E.g., B alleles more likely with A alleles than b alleles are with A alleles Equilibrium - alleles A locus, A allele p = 15/25 = 0.6 a allele q = 1-p = 0.4 B locus, B allele p = 20/25 = 0.8; b allele q = 1-p = 0.2 Equilibrium - haplotypes Allele B with allele A = 12; A without B = 3 times; AB 12/15 = 0.8 Allele B with allele a = 8; a without B = 2 times; aB 8/10 = 0.8 Equilibrium graphically Disequilibrium - alleles
    [Show full text]
  • Design and Analysis of Genetic Association Studies
    ection S ON Design and Analysis of Statistical Genetic Association Genetics Studies Hemant K Tiwari, Ph.D. Professor & Head Section on Statistical Genetics Department of Biostatistics School of Public Health Association Analysis • Linkage Analysis used to be the first step in gene mapping process • Closely located SNPs to disease locus may co- segregate due to linkage disequilibrium i.e. allelic association due to linkage. • The allelic association forms the theoretical basis for association mapping Linkage vs. Association • Linkage analysis is based on pedigree data (within family) • Association analysis is based on population data (across families) • Linkage analyses rely on recombination events • Association analyses rely on linkage disequilibrium • The statistic in linkage analysis is the count of the number of recombinants and non-recombinants • The statistical method for association analysis is “statistical correlation” between Allele at a locus with the trait Linkage Disequilibrium • Over time, meiotic events and ensuing recombination between loci should return alleles to equilibrium. • But, marker alleles initially close (genetically linked) to the disease allele will generally remain nearby for longer periods of time due to reduced recombination. • This is disequilibrium due to linkage, or “linkage disequilibrium” (LD). Linkage Disequilibrium (LD) • Chromosomes are mosaics Ancestor • Tightly linked markers Present-day – Alleles associated – Reflect ancestral haplotypes • Shaped by – Recombination history – Mutation, Drift Tishkoff
    [Show full text]
  • Linkage Disequilibrium Fine Mapping of Quantitative Trait Loci
    Genet. Sel. Evol. 35 (2003) 513–532 513 © INRA, EDP Sciences, 2003 DOI: 10.1051/gse:2003037 Original article Linkage disequilibrium fine mapping of quantitative trait loci: A simulation study a∗ b Jihad M. ABDALLAH , Bruno GOFFINET , b a Christine CIERCO-AYROLLES , Miguel PÉREZ-ENCISO a Station d’amélioration génétique des animaux, Institut national de la recherche agronomique, Auzeville BP 27, 31326 Castanet-Tolosan Cedex, France b Unité de biométrie et intelligence artificielle, Institut national de la recherche agronomique, Auzeville BP 27, 31326 Castanet-Tolosan Cedex, France (Received 27 June 2002; accepted 17 January 2003) Abstract – Recently, the use of linkage disequilibrium (LD) to locate genes which affect quantitative traits (QTL) has received an increasing interest, but the plausibility of fine mapping using linkage disequilibrium techniques for QTL has not been well studied. The main objectives of this work were to (1) measure the extent and pattern of LD between a putative QTL and nearby markers in finite populations and (2) investigate the usefulness of LD in fine mapping QTL in simulated populations using a dense map of multiallelic or biallelic marker loci. The test of association between a marker and QTL and the power of the test were calculated based on single- marker regression analysis. The results show the presence of substantial linkage disequilibrium with closely linked marker loci after 100 to 200 generations of random mating. Although the power to test the association with a frequent QTL of large effect was satisfactory, the power was low for the QTL with a small effect and/or low frequency. More powerful, multi-locus methods may be required to map low frequent QTL with small genetic effects, as well as combining both linkage and linkage disequilibrium information.
    [Show full text]
  • Unbiased Estimation of Linkage Disequilibrium from Unphased Data
    bioRxiv preprint doi: https://doi.org/10.1101/557488; this version posted August 8, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Unbiased estimation of linkage disequilibrium from unphased data * 2 Aaron P. Ragsdale and Simon Gravel 3 Department of Human Genetics, McGill University, Montreal, QC, Canada * 4 [email protected] 5 August 8, 2019 6 Abstract 7 Linkage disequilibrium is used to infer evolutionary history, to identify genomic regions under selection, 8 and to dissect the relationship between genotype and phenotype. In each case, we require accurate 9 estimates of linkage disequilibrium statistics from sequencing data. Unphased data present a challenge 10 because multi-locus haplotypes cannot be inferred exactly. Widely used estimators for the common statis- 2 2 11 tics r and D exhibit large and variable upward biases that complicate interpretation and comparison 12 across cohorts. Here, we show how to find unbiased estimators for a wide range of two-locus statistics, 2 13 including D , for both single and multiple randomly mating populations. These unbiased statistics are 14 particularly well suited to estimate effective population sizes from unlinked loci in small populations. We 15 develop a simple inference pipeline and use it to refine estimates of recent effective population sizes of 16 the threatened Channel Island Fox populations. 17 Introduction 18 Linkage disequilibrium (LD), the association of alleles between two loci, is informative about evolutionary 19 and biological processes.
    [Show full text]
  • Linkage Disequilibrium and Heterozygosity Modulate the Genetic Architecture of Human Complex Phenotypes
    bioRxiv preprint doi: https://doi.org/10.1101/705285; this version posted August 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Linkage Disequilibrium and Heterozygosity Modulate the Genetic Architecture of Human Complex Phenotypes Dominic Hollanda,b,∗, Oleksandr Freid, Rahul Desikanc, Chun-Chieh Fana,e,f, Alexey A. Shadrind, Olav B. Smelanda,d,g, Ole A. Andreassend,g, Anders M. Dalea,b,f,h aCenter for Multimodal Imaging and Genetics, University of California at San Diego, La Jolla, CA 92037, USA, bDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA, cDepartment of Radiology, University of California, San Francisco, San Francisco, CA 94158, USA, dNORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo 0424 Oslo, Norway, eDepartment of Cognitive Sciences, University of California at San Diego, La Jolla, CA 92093, USA, fDepartment of Radiology, University of California, San Diego, La Jolla, CA 92093, USA, gDivision of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway, hDepartment of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA, Abstract We propose an extended Gaussian mixture model for the distribution of causal effects of common single nucleotide polymorphisms (SNPs) for human complex phenotypes, taking into account linkage disequilibrium (LD) and heterozy- gosity (H), while also allowing for independent components for small and large effects. Using a precise methodology showing how genome-wide association studies (GWAS) summary statistics (z-scores) arise through LD with underlying causal SNPs, we applied the model to multiple GWAS.
    [Show full text]
  • Genetic Diversity and Fitness in Small Populations of Partially Asexual, Self
    Heredity (2010) 104, 482–492 & 2010 Macmillan Publishers Limited All rights reserved 0018-067X/10 $32.00 www.nature.com/hdy ORIGINAL ARTICLE Genetic diversity and fitness in small populations of partially asexual, self-incompatible plants M Navascue´s1,2, S Stoeckel3 and S Mariette4 1Unidad de Gene´tica, Centro de Investigacio´n Forestal, INIA, Carretera de La Corun˜a km 7.5, Madrid, Spain; 2E´ quipe E´ co-e´volution Mathe´matique, CNRS, UMR 7625 E´ cologie et E´ volution, Universite´ Pierre et Marie Curie & E´ cole Normale Supe´rieure, Paris, France; 3UMR Biology of Organisms and Populations applied to Plant Protection, INRA Agrocampus Rennes, Le Rheu, France and 4Unite´ de Recherche sur les Espe`ces Fruitie`res, INRA, Domaine de la Grande Ferrade, Villenave d’Ornon, France How self-incompatibility systems are maintained in plant S-locus. In addition, an excess of heterozygotes was present in populations is still a debated issue. Theoretical models predict the population, causing an increase in mutation load. This that self-incompatibility systems break down according to the heterozygote excess was enhanced by the self-incompatibility intensity of inbreeding depression and number of S-alleles. system in small populations. In addition, in highly asexual Other studies have explored the function of asexual reproduc- populations, individuals produced asexually had some fitness tion in the maintenance of self-incompatibility. However, the advantages over individuals produced sexually, because population genetics of partially asexual, self-incompatible sexual reproduction produces homozygotes of the deleterious populations are poorly understood and previous studies have allele, contrary to asexual reproduction. Our results suggest failed to consider all possible effects of asexual reproduction or that future research on the function of asexuality for the could only speculate on those effects.
    [Show full text]