Professor of Genetics, Psychiatry, and Ecology & Evolutionary Biology

* B.A. University of Southern California, 1965
* Ph.D. University of Wisconsin, 1969

Research Interests:

* Complex Human Disorders
* Neuropsychiatric Disorders
* Human Population Genetics
* Human Evolution

Honors:

* Fellow, American Association for the Advancement of Science
* Mellon Distinguished Visiting Professor, University of Witwatersrand, South Africa
* Carter Medal and Lecture, British Society of Human Genetics
* "Profiles in DNA Courage" award, U.S. National Institute of Justice
* "Biomedical Paper of the Year (2002)” by The Lancet for Rosenberg et al. 2002

Current Research:

Normal 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 search for the genes for several inherited disorders, including neuropsychiatric disorders, and working on statistical methods to analyze the data. We are also studying these polymorphisms 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.

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 efforts to find genes responsible for neuropsychiatric disorders have most recently focused on Giles de la Tourette Syndrome, but studies of schizophrenia are also ongoing. In both cases, we have family data, collected in collaboration with many other investigators, on which extensive diagnostic evaluations have been completed. Complete 10 cM genome scans have been completed on most of the large kindreds and sets of small families. While no locus appears to account for all cases of Gilles Tourette Syndrome, we have strong evidence of a predisposing genetic factor on the distal long arm of chromosome 17. Studies are ongoing to narrow the region and identify the relevant variant.

We are also 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 40 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.

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.

Polymorphic patterns for the alpha satellite repetitive DNA on chromosome 17. The commonly seen polymorphism, using Pvu II to digest genomic DNA of Caucasians, is the presence or absence of a tandemly repeated sequence of 2.2kb, as illustrated in the first two lanes. We have found several new variant phenotypes in African pygmies, as illustrated in lanes 3 through 7 where band intensity is related to number of copies of a unit of that length.