title: Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3.
abstract: In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.
authors.affiliation: Division of Gastroenterology, Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri 63110, USA.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Geahlen
authors.forename: Carlo
authors.initials: C
authors.lastname: Lapid
authors.forename: Kaisa
authors.initials: K
authors.lastname: Thorell
authors.forename: Igor
authors.initials: I
authors.lastname: Nikolskiy
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Huh
authors.forename: Edward L
authors.initials: EL
authors.lastname: Oates
authors.forename: Jochen K M
authors.initials: JK
authors.lastname: Lennerz
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tian
authors.forename: Victoria G
authors.initials: VG
authors.lastname: Weis
authors.forename: Shradha S
authors.initials: SS
authors.lastname: Khurana
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Lundin
authors.forename: Alan R
authors.initials: AR
authors.lastname: Templeton
authors.forename: Jason C
authors.initials: JC
authors.lastname: Mills
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D019143:Evolution, Molecular; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism; D056426:Genetic Loci / Q000235:genetics*; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D008253:Macaca mulatta / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011544:Pseudogenes / Q000235:genetics*; D044469:Racial Groups / Q000235:genetics*; D012641:Selection, Genetic / Q000235:genetics*; D013045:Species Specificity; D034421:Sus scrofa / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; C549164:GKN3P protein, human; D008565:Membrane Proteins; C549163:gastrokine 3 protein, mouse
keywords: 1000 Genomes data; BRICHOS domain; population genetics; selective sweeps