Genomic organization and sequence variation of the human integrin subunit alpha8 gene (ITGA8).
The integrin alpha8 is highly expressed during kidney and lung development. alpha8-deficient mice display abnormal renal development suggesting that alpha8 plays a critical role in organogenesis. Therefore, it would be of considerable interest to understand the genomic structure, localization and sequence variation of the alpha8 gene. Using FISH and genomic database analysis, we show that alpha8 gene maps to chromosome 10p13 and consists of >200 kbp organized into 30 exons. Examination of 47 individuals from two different ethnic groups (European and African descent) identified 286 varying sites. The diversity of alpha8 is comparable to that of other regions within the human genome. Eight of the varying sites were located in the coding regions: six resulted in nonsynonymous substitutions of which two lead to non-conservative changes in protein. None of the sites showed significant deviation from Hardy-Weinberg equilibrium. We mapped the coding region single nucleotide polymorphisms (SNPs) onto a model of the predicted alpha8 structure and found all the SNPs were located in the "calf" of the extracellular domain. In the European population, the linkage disequilibrium statistic D' showed three blocks of relatively non-recombinant regions in the alpha8 gene while the African population showed more evidence of recombination. The observed patterns of the linkage disequilibrium statistic R2 suggest that a large number of sites will need to be genotyped to ensure coverage of the entire gene for genetic association studies. Identification of the sequence variation will allow genetic association studies of alpha8 in kidney and lung disease.
Ekwa-Ekoka
Catherine
C
Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA.
Diaz
George A
GA
Carlson
Chris
C
Hasegawa
Tomonobu
T
Samudrala
Ram
R
Lim
Kim-Chew
KC
Yabu
Julie M
JM
Levy
Brynn
B
Schnapp
Lynn M
LM
D001483:Base Sequence; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D030541:Databases, Genetic; D005091:Exons; D014644:Genetic Variation; D016678:Genome; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D039001:Integrin alpha Chains / Q000235:genetics* / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D015810:Linkage Disequilibrium; D008168:Lung / Q000378:metabolism; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid
D018076:DNA, Complementary; D039001:Integrin alpha Chains; C093856:integrin alpha8; D004247:DNA