Corticotropin releasing hormone (CRH) gene variation: comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines.

TitleCorticotropin releasing hormone (CRH) gene variation: comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines.
Publication TypeJournal Article
Year of Publication2007
AuthorsShimmin, LC, Natarajan, S, Ibarguen, H, Montasser, M, Kim, D-K, Hanis, CL, Boerwinkle, E, Wadhwa, PD, Hixson, JE
JournalDNA Seq
Volume18
Issue6
Pagination434-44
Date Published2007 Dec
ISSN1042-5179
KeywordsAnimals, Base Sequence, Cell Line, Corticotropin-Releasing Hormone, Ethnic Groups, Female, Haplotypes, Humans, Hybrid Cells, Linkage Disequilibrium, Male, Mice, Molecular Sequence Data, Monosomy, Phylogeny, Polymorphism, Single Nucleotide, Sequence Analysis, DNA
Abstract

Candidate gene association studies have met with mixed success due to many reasons including incomplete surveys of genetic variation and differences in patterns of genetic variation among study populations. We present the results of comprehensive variant discovery for the corticotropin releasing hormone gene (CRH on chromosome 8) encoding a neuropeptide that is central to many physiologic pathways. Mouse-human hybrid cell lines were constructed that are monosomic for human chromosome 8 for resequencing of separated CRH alleles to identify variants and directly determine their chromosomal phase for three major ethnic groups including African Americans (AA), Mexican Americans (MA) and European Americans (EA). We also resequenced diploid individuals to evaluate single nucleotide polymorphism (SNP) discovery in the limited numbers of monosomic hybrid cell lines. Our results show that CRH variation is very different in AA, yielding larger numbers of variants and haplotypes compared to MA and EA. Analysis of LD structure found three haplotype blocks in AA and two blocks in EA. Comparisons between AA and EA groups yielded extremely high measures of genetic differentiation (Wright's F(ST)>0.6), likely reflecting disruptive selection in CRH evolution. Network analysis showed that AA have retained an ancestral CRH haplotype, while the most common EA haplotype is derived from a single recombination event.

DOI10.1080/10425170701388719
Alternate JournalDNA Seq.
PubMed ID17676473
Grant ListP01 HD047609 / HD / NICHD NIH HHS / United States