PSB 2002 Tutorial

PSB 2002

Human Genetic Variation

Description

With availability of a nearly complete reference sequence of the human genome, attention is now being directed toward the normal and abnormal variation in the DNA sequence. Because of the importance of the normal variation for studies designed to identify and characterize the abnormal variation causing disorders as well as for studies designed to illuminate human evolution, a basic tutorial on human genetic variation is timely.

The tutorial will be divided into three segments:

• a brief introduction to the types of DNA sequence variation with the special mutational and typing characteristics of each individual type and the special characteristics of haplotypes;
• an overview of the empiric distributions of variation according to location in the genome and among populations; and
• an introduction to the theory and analytic methods with a special emphasis on haplotypes and linkage disequilibrium.

I. Introduction to the types of variation: SNPs, STRPs, VNTRs, InDels, haplotypes

This section will review the natures of the different types of polymorphisms, the mutational mechanisms generating them, and the different detection methods used for typing individuals. Discussion will emphasize the relative values of each type of polymorphism for different research objectives and the types of laboratory errors that can occur and confound interpretation if not considered in analyses.

II. An overview of distribution of variation in the genome and the species

This section will rely heavily on ALFRED for examples of population variation and on other databases (e.g., dbSNP, HGBASE) for genomic distributions. The evolutionary population genetics factors believed responsible for the global pattern of variation will be summarized. The biological factors that may be responsible for the genomic distributions will also be discussed. The special nature of the HLA system will be summarized.

III. Theory and analytic methods: Random genetic drift, selection, frequency estimation, linkage disequilibrium, etc.

This section will build upon the largely descriptive previous sections to present research questions and the statistical methods available to address them. The theory underlying various statistical methods will be discussed with a special emphasis on the assumptions and the degree to which they apply to Homo sapiens. Because of the current interest in linkage disequilibrium, a substantial portion of the section will deal with why disequilibrium is important, with haplotype inference, and with the various statistical measures of disequilibrium.

Biographical Sketches:

Kenneth K. Kidd is Professor of Genetics, Yale University School of Medicine. Since obtaining his Ph.D. in Genetics he has worked in many areas of human genetics from theoretical population genetics to positional cloning, accumulating over 400 publications. During the past decade a major portion of his research, in collaboration with J.R. Kidd, has focused on human population genetics with a current emphasis on linkage disequilibrium. He was senior author of the PSB2000 paper on an allele frequency database, ALFRED, and continues to direct the enhancement of that Web-accessible reference database.

Judith R. Kidd is Research Scientist in the Department of Genetics, Yale University School of Medicine. In addition to a Ph.D. in Anthropology she is a molecular biologist actively working at the bench. For the past 15 years she has focused on using normal human molecular genetic variation among populations from all major geographic regions of the world to study recent human evolution.

Glenys Thomson, Professor of Genetics, Department of Integrative Biology, University of California, Berkeley, received her Ph.D. in Statistics and then, as a postdoctoral fellow, began her special focus of over two decades on the statistical population genetics of HLA, the major histocompatibility complex in humans. She is currently in charge of the Biostatistical Genetics Core for the upcoming 13^th International Histocompatibility Workshop. In addition to her ongoing theoretical genetics work she is actively involved in collecting empiric data on linkage disequilibrium in humans.