Abstract
CLEC4M is a C-type lectin gene serving as cell adhesion receptor and pathogen recognition receptor. It recognizes several pathogens of important public health concern. In particular, a highly polymorphic variable number tandem repeat (VNTR) at the neck-region of CLEC4M had been associated with genetic predisposition to some infectious diseases. To gain insight into the origin and evolution of this VNTR in CLEC4M, we studied 21 Africans, 20 Middle Easterns, 35 Europeans, 38 Asians, 13 Oceania, and 18 Americans (a total of 290 chromosomes) from the (Human Genome Diversity Panel) HGDP-CEPH panel; these samples covered most of alleles of this VNTR locus present in human populations. We identified a limited number of haplotypes among the basic repeat subunits that is 69 base pairs in length. Only 8 haplotypes were found. Their sequence identities were determined in the 290 chromosomes. VNTR alleles of different repeat length (from 4 to 9 repeats) were analyzed for composition and orientation of these subunits. Our results showed that the subunit configuration of the same repeat number of VNTR locus from different populations were, in fact, virtually identical. It implies that most of the VNTR alleles existed before dispersion of modern humans outside Africa. Further analyses indicate that the present diversity profile of this locus in worldwide populations is generated from the effect of migration of different tribes and neutral evolution. Our findings do not support the hypothesis that the origin of the VNTR alleles were arisen by independent (separate) mutation events and caused by differential allele advantage and natural selection as suggested by previous report based on SNP data.
Highlights
Dendritic cell-specific intracellular adhesion molecular-3grabbing nonintegrin (CLEC4L) and L-SIGN called DCSIGN related (CLEC4M) are C-type lectins involved in both innate and adaptive immunity
With regards to CLEC4M, it serves as a receptor for a variety of viruses, including HIV-1, hepatitis C, Ebola, and SARS-coronavirus, as well as the parasite Schistosoma mansoni and bacteria
This 26-kb segment is believed to arise as a result of a duplication of an ancestral gene [8]. These two genes in the cluster share a high degree of homology [2]. Both proteins are organized into three domains: (1) an N-terminal cytoplasmic region with a di-leucine motif for internalization followed by a transmembrane domain, (2) a C-terminal extracellular domain with a C-type carbohydrate recognition domain (CRD) involved in pathogen binding, and (3) a neckregion containing variable number of repeats of conserved subunit of 23-amino-acid sequence, that connects the CRD to the transmembrane region
Summary
Dendritic cell-specific intracellular adhesion molecular-3grabbing nonintegrin (CLEC4L) and L-SIGN called DCSIGN related (CLEC4M) are C-type lectins involved in both innate and adaptive immunity. Our results showed that the haplotype of subunits of the same VNTR (from 4 to 9 repeats) sampled from subjects of different continents were virtually identical, which implied the different VNTR alleles in CLEC4M gene had existed for a long time, at least before the date of ‘‘out-of-Africa’’ event.
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