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. 2022 Apr 1;25(5):104189.
doi: 10.1016/j.isci.2022.104189. eCollection 2022 May 20.

Balancing selection at the human salivary agglutinin gene (DMBT1) driven by host-microbe interactions

Adel F Alharbi  1   2 , Nongfei Sheng  3 , Katie Nicol  1 , Nicklas Strömberg  3 , Edward J Hollox  1
Affiliations

Balancing selection at the human salivary agglutinin gene (DMBT1) driven by host-microbe interactions

Adel F Alharbi et al. iScience. .

Abstract

Discovering loci under balancing selection in humans can identify loci with alleles that affect response to the environment and disease. Genome variation data have identified the 5' region of the DMBT1 gene as undergoing balancing selection in humans. DMBT1 encodes the pattern-recognition glycoprotein DMBT1, also known as SALSA, gp340, or salivary agglutinin. DMBT1 binds to a variety of pathogens through a tandemly arranged scavenger receptor cysteine-rich (SRCR) domain, with the number of domains polymorphic in humans. We show that the signal of balancing selection is driven by one haplotype usually carrying a shorter SRCR repeat and another usually carrying a longer SRCR repeat. DMBT1 encoded by a shorter SRCR repeat allele does not bind a cariogenic and invasive Streptococcus mutans strain, in contrast to the long SRCR allele that shows binding. Our results suggest that balancing selection at DMBT1 is due to host-microbe interactions of encoded SRCR tandem repeat alleles.

Keywords: biological sciences; evolutionary mechanisms; genetics.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Evidence for balancing selection at the human DMBT1 gene The DMBT1 gene is shown in blue, with three tracks above representing Tajima’s D measured from sequenced genomes from three populations (European-Americans from Utah (CEU) in green, Chinese from Beijing (CHB) in blue, Yoruba from Ibadan (YRI) in orange), image taken from the 1000 Genomes selection browser (https://hsb.upf.edu/). Below the DMBT1 gene the SNP rs11523871 and two CNVs thar affect the copy number of the SRCR repeats are shown. Above the tracks showing Tajima’s D are different sources of evidence of balancing selection, namely the beta statistic (Siewert and Voight, 2017), the NCD statistic (purple (Bitarello et al., 2018), trans-specific variants (Leffler et al., 2013), and composite likelihood ratio tests (DeGiorgio et al., 2014).
Figure 2
Figure 2
Association of rs11523871 and DMBT1 SRCR repeat copy number (A and B) For two populations, CEPH (A) and YRI (B), the distributions of DMBT1 SRCR repeat domain copy numbers associated with the rs11523871-A allele (blue, above the x axis) and rs11523871-C (red, below the x axis) are shown. The y axis shows the number of observations in the two samples (CEPH n = 263, YRI n = 116).
Figure 3
Figure 3
DMBT1 gene expression and rs11523871 genotype (A) Tissue expression of DMBT1 across 54 tissues, ordered by mean expression level, from RNAseq data. Data and image from the GTEx Portal Locus Browser v.8. (B) Violin plots show rs11523871 genotype and expression level for the three tissues showing a statistically significant relationship. Median and interquartile range are shown by the white line and grey box. (C) Boxplots showing rs11523871 genotype and expression level in duodenum from 41 healthy patients, normalized against two different housekeeping genes. Left boxplot shows data normalized to RPLP0 expression; right boxplot shows data normalized to UBC expression. Boxplots indicate median, interquartile range, and range.
Figure 4
Figure 4
Identification of transcripts spanning the SRCR repeats in DMBT1 The DMBT1 allele from the genome assembly, with 14 tandemly arranged SRCR repeats highlighted in blue, is shown at the top of the figure, with GRCh38 coordinates as a scale immediately underneath. The sequence alignment of single-molecule sequencing reads mapping to the DMBT1 gene are shown, with at the bottom, the genome features format file (GFF) derived from the sequence alignments. In the GFF image, black boxes indicate complete SRCR repeats, with the total number of tandemly repeated SRCR repeats for that transcript highlighted in red on the left of the particular transcript.
Figure 5
Figure 5
Differential binding of S. mutans by DMBT1 isoforms in saliva Blots of SDS-PAGE gels with saliva from different individuals with DMBT1 size isoforms I–IV. (A and B) (A) probed using a biotinylated S. mutans SpaP A, Cnm strain and (B) probed with DMBT1-specific antibodies. The positions of DMBT1 on both blots is indicated. Note that DMBT1 isoform size differences are not seen, as they are not resolved at the SDS-PAGE gel density used before the blotting.
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