Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The whey acidic protein four-disulfide core (WFDC) gene cluster on human chromosome 20q13, harbors 15 small serine protease inhibitor genes with roles in innate immunity, reproduction, and regulation of endogenous proteases kallikreins. The WFDC cluster has emerged as a prime example of rapid diversification and adaptive evolution in primates. This study sought a better understanding of the evolutionary history of WFDC genes in humans and focused on exploring the adaptive selection signatures found in populations of European (Utah residents with ancestry from northern and western Europe [CEU]) and African (Yoruba from Ibadan, in Nigeria [YRI]) ancestry in a genome-wide scan for putative targets of recent adaptive selection. Our approach included resequencing coding and noncoding regions of WFDC6, EPPIN, and WFDC8 in 20 CEU and of SPINT4 in 20 YRI individuals. We generated 302 kb and 60 kb of high-quality sequence data from CEU and of YRI populations, respectively, enabling the identification of 72 single nucleotide polymorphisms. Using classic neutrality tests, empirical and haplotype-based analysis, we pinpointed WFDC8 and SPINT4 as the likely targets of short-term balancing selection in the CEU population, and recent positive selection (incomplete selective sweep) in the YRI population. Putative candidate variants targeted by selection include 44A (rs7273669A) for WFDC8, which may downregulate gene expression by abolishing the binding site of two transcription factors; and a haplotype configuration [Ser73+98A] (rs6017667A-rs6032474A) for SPINT4, which may simultaneously affect protein function and gene regulation. We propose that the evolution of WFDC8 and SPINT4 has been shaped by complex selective scenarios due to the interdependence of variant fitness and ecological variables.
Mol Biol Evol 2011 Oct
PMID:Differing evolutionary histories of WFDC8 (short-term balancing) in Europeans and SPINT4 (incomplete selective sweep) in Africans. 2153 19

WFDC (Whey Acidic Protein Four Disulfide Core)-containing proteins have been reported in many species, yet they remain uncharacterized in the rat. In this study, we report the identification and characterization of four rat Wfdc genes, Wfdc6a, Wfdc8, Wfdc11 and Wfdc16. Their expression profile in a variety of tissues including the male reproductive tract is analyzed. Wfdc8, Wfdc11 and Wfdc16 expression is confined to the epididymis, while Wfdc6a is expressed widely. Since gene expression in the male reproductive tract is largely androgen-dependent, Wfdc expression was analyzed in the developing (20-60-day-old) and castrated rats. Their expression pattern in developing rats does not correlate with changes in testosterone. Wfdc genes are, however, down-regulated in castrated adult rats, indicating that their dependence on androgens for expression is more pronounced in the adult than in the developing rat. To test the anti-microbial potential of WFDC8, a recombinant WFDC8 C-terminal protein was produced, which exhibited potent anti-bacterial activity against Eschericia coli. Induction of anti-microbial genes is one of the responses during infections in many organ systems. To determine if WFDCs form the components of male reproductive tract innate immunity, Wfdc8 expression pattern was observed in rats challenged with lipopolysaccharide (LPS). For the first time we report the induction of Wfdc8 gene expression in LPS-treated rats, indicating their contributions to the innate immune functions of the male reproductive tract.
Mol Reprod Dev 2011 Sep
PMID:Identification and characterization of Wfdc gene expression in the male reproductive tract of the rat. 2179 15

The whey acidic protein (WAP) four-disulfide core domain (WFDC) locus located on human chromosome 20q13 spans 19 genes with WAP and/or Kunitz domains. These genes participate in antimicrobial, immune, and tissue homoeostasis activities. Neighboring SEMG genes encode seminal proteins Semenogelin 1 and 2 (SEMG1 and SEMG2). WFDC and SEMG genes have a strikingly high rate of amino acid replacement (dN/dS), indicative of responses to adaptive pressures during vertebrate evolution. To better understand the selection pressures acting on WFDC genes in human populations, we resequenced 18 genes and 54 noncoding segments in 71 European (CEU), African (YRI), and Asian (CHB + JPT) individuals. Overall, we identified 484 single-nucleotide polymorphisms (SNPs), including 65 coding variants (of which 49 are nonsynonymous differences). Using classic neutrality tests, we confirmed the signature of short-term balancing selection on WFDC8 in Europeans and a signature of positive selection spanning genes PI3, SEMG1, SEMG2, and SLPI. Associated with the latter signal, we identified an unusually homogeneous-derived 100-kb haplotype with a frequency of 88% in Asian populations. A putative candidate variant targeted by selection is Thr56Ser in SEMG1, which may alter the proteolytic profile of SEMG1 and antimicrobial activities of semen. All the well-characterized genes residing in the WDFC locus encode proteins that appear to have a role in immunity and/or fertility, two processes that are often associated with adaptive evolution. This study provides further evidence that the WFDC and SEMG loci have been under strong adaptive pressure within the short timescale of modern humans.
Mol Biol Evol 2013 Apr
PMID:Reproduction and immunity-driven natural selection in the human WFDC locus. 2329 42