Homozygosity disequilibrium and its applications


Hsin-Chou Yang

15:40:00 - 16:30:00

308 , Mathematics Research Center Building (ori. New Math. Bldg.)

Homozygosity disequilibrium (HD) defined by a sizable tract of homozygosity deviated from a random distribution in the genome plays important roles in population genomics and medical genomics. We developed computational procedures to detect genomic segments bearing HD, identify samples with structural alterations and/or unusual genotypic patterns, and cluster samples with close HD structure by analyzing data of genome-wide SNP arrays. The algorithms were packaged into user-friendly software, LOHAS (Loss-Of-Heterozygosity Analysis Suite), written in R and R GUI ( tm). Case studies in population genomics (30 African trios, 30 Caucasian trios and 90 independent Asian samples in the HapMap project II), cancer genomics (304 patients and 50 normal controls in an acute lymphoblastic leukaemia (ALL) study) and medical genomics (2,000 patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium and 868 patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium in two rheumatoid arthritis (RA) studies) are presented in this talk. All individuals studied were genotyped with either Affymetrix GeneChip 500K Set or Illumina BeadChip 550K Set. Our analysis of the HapMap project II data identifies frequent regions of long contiguous stretches of homozygosity, e.g., the region that encompasses the centromeric gene desert region of chromosome 16, indicative of non-random mating and/or meiotic recombination cold spots and separated samples with different genetic backgrounds. Analysis of the ALL data identifies common gene regions of loss of heterozygosity, e.g., ETV6 and CDKN1B, and distinguished cancer patients and normal samples or cluster disease subtypes by use of HD patterns. Analysis of the two RA data sets consistently pinpoints two regions within the human major histocompatibility complex region containing RA- associated recessive-acting susceptibility genes, e.g., HLA- DRB1 and HLA-DPB1. In conclusion, identification of HD regions facilitates to localize genomic regions undergoing selection, recessive-acting susceptibility genes, and tumor suppressor genes, providing insights to the genetic background of worldwide populations and genetic mechanism of complex diseases