Africa; China; Gambia; Genetics; India; Psychiatry; Global Health; Neuropsychiatry
The majority of the work in my laboratory is currently focused on human genome diversity: the patterns of normal genetic variation among four dozen populations (~2500 individuals) from around the world, the variation in those patterns along the genome, and the inference of recent human evolutionary processes. The research involves both molecular and biostatistical components. Because of longstanding interest in neuropsychiatric disorders that fail to show a Mendelian pattern but do "run in families," our genome diversity studies include sequence variation at several genes with important neurologic functions, candidate genes for various neuropsychiatric disorders, and genes demonstrated to be associated with alcoholism. Managing these genotype and allele frequency data and making them publicly available has also involved us in a major bioinformatics effort: ALFRED, the allele frequency database we have developed. That database, illustrations of our human evolution findings, recent publications, and other material can be accessed through the Lab’s website.
Specialized Terms: Complex Human Disorders; Neuropsychiatric Disorders; Human Population ; Genetics; Human Evolution
Extensive Research DescriptionNormal DNA sequence variation such as single nucleotide polymorphisms (SNPs), short tandem repeat polymorphisms (STRPs), etc. have made Homo sapiens amenable to many types of genetic analysis. We are using these polymorphisms to study the genes for several inherited disorders, including neuropsychiatric disorders, and working on statistical methods to analyze the data. We are studying these and other polymorphisms genome-wide on DNA samples from many different human populations with an emphasis on understanding the organization of normal variation including studies of linkage disequilibrium and estimates of the distribution of the variation in the entire species. We have established a database, ALFRED, the ALelle FREquency Database, to accumulate allele frequencies of DNA polymorphisms. A current focus is on forensic uses of SNPs.
For the past several years my laboratory has studied the genetics of complex human disorders, those disorders that fail to show a Mendelian pattern but do "run in families". DNA polymorphisms are now being used to search for the genetic loci of major effect in behavioral and other complex disorders. Our previous efforts focused on finding genes responsible for neuropsychiatric disorders, especially Giles de la Tourette Syndrome and schizophrenia. While no locus appears to account for all cases of Tourette Syndrome, we have strong evidence of a predisposing genetic factor on the distal long arm of chromosome 17. Studies are ongoing through collaborations to narrow the region and identify the relevant variant.
We are studying the population genetics of expressed and non-expressed genetic variation at several genes of known neurologic relevance, such as the dopamine receptors D2 and D4 and the enzyme COMT, Catechol-O-methyl transferase. Also, because of their demonstrated relevance to alcoholism we are studying the genes involved in ethanol metabolism, the ADH genes and ALDH2. Understanding the nature of the common normal variation at these loci provides a background for investigating how they might influence normal and abnormal neurologic/metabolic function and susceptibility to psychiatric disorders. The duplicated ADH Class 1 genes are unique to primates and are the focus of molecular evolution studies. Several more evolution-oriented projects are also being pursued. These include theoretical studies as well as studying samples from diverse human populations for DNA polymorphisms. For some genes of interest we are also collecting DNA sequence of other great apes to examine the origins of the human lineage.
The lab's efforts are currently focused on genome diversity among world populations and understanding how that diversity arose. We have accumulated cell lines on individuals from over 45 different populations and plan to increase this resource in the coming years. On a global basis we are finding that the majority of alleles for nuclear DNA polymorphisms are present in most populations around the world, though sub-Saharan African populations have more genetic variation (alleles), in general, than indigenous populations in any other part of the world. We interpret the data to mean that there was a major founder effect and loss of variation associated with the expansion of modern humans out of Africa. Haplotype data collected on all of the populations we are studying are beginning to reveal patterns that provide a better understanding of that founder effect and the recent evolutionary history of modern humans. Recent studies have used these resources to select SNPs that can be useful in forensics, both for individual identification (matching the DNA at a crime scene with a suspect's DNA). Other SNPs are being selected for their value in inference of ancestry from an individual's DNA.
Bioinformatics research, in collaboration with the Yale Center for Medical Informatics, is ongoing in two areas. We are working to improve data management for the extensive marker typing results accumulating on many of the projects. We are also working to improve the utility of data in ALFRED through new search and display modes as well as relevant links to other online sources
- Gene study using polymorphism of the DNA for several inherited disorders
- Collaborative study to narrow the region and identify the chromosome involved in Tourette syndrome and Schizophrenia
- Population genetics of expressed and non-expressed genetic variation at several genes of known neurologic relevance
- Bioinformatics research to improve data management for extensive marker typing results and improve the utility of data in ALFRED
Origin and dispersal of atypical aldehyde dehydrogenase ALDH2487Lys.
Luo HR, Wu GS, Pakstis AJ, Tong L, Oota H, Kidd KK, Zhang YP. Origin and dispersal of atypical aldehyde dehydrogenase ALDH2487Lys. Gene 2009, 435:96-103.
Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant.
Li H, Borinskaya S, Yoshimura K, Kal'ina N, Marusin A, Stepanov VA, Qin Z, Khaliq S, Lee MY, Yang Y, Mohyuddin A, Gurwitz D, Mehdi SQ, Rogaev E, Jin L, Yankovsky NK, Kidd JR, Kidd KK. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Annals Of Human Genetics 2009, 73:335-45.
Global variation in CYP2C8-CYP2C9 functional haplotypes.
Speed WC, Kang SP, Tuck DP, Harris LN, Kidd KK. Global variation in CYP2C8-CYP2C9 functional haplotypes. The Pharmacogenomics Journal 2009, 9:283-90.
Inferring the demographic history of African farmers and pygmy hunter-gatherers using a multilocus resequencing data set.
Patin E, Laval G, Barreiro LB, Salas A, Semino O, Santachiara-Benerecetti S, Kidd KK, Kidd JR, Van der Veen L, Hombert JM, Gessain A, Froment A, Bahuchet S, Heyer E, Quintana-Murci L. Inferring the demographic history of African farmers and pygmy hunter-gatherers using a multilocus resequencing data set. PLoS Genetics 2009, 5:e1000448.
Signatures of purifying and local positive selection in human miRNAs.
Quach H, Barreiro LB, Laval G, Zidane N, Patin E, Kidd KK, Kidd JR, Bouchier C, Veuille M, Antoniewski C, Quintana-Murci L. Signatures of purifying and local positive selection in human miRNAs. American Journal Of Human Genetics 2009, 84:316-27.
Semantic Web-based integration of cancer pathways and allele frequency data.
Holford ME, Rajeevan H, Zhao H, Kidd KK, Cheung KH. Semantic Web-based integration of cancer pathways and allele frequency data. Cancer Informatics 2009, 8:19-30.
Population-specific variation in haplotype composition and heterozygosity at the POLB locus.
Yamtich J, Speed WC, Straka E, Kidd JR, Sweasy JB, Kidd KK. Population-specific variation in haplotype composition and heterozygosity at the POLB locus. DNA Repair 2009, 8:579-84.