Stabilizing selection on microsatellite allele length at arginine vasopressin 1a receptor and oxytocin receptor loci

Watts, Phillip C.; Kallio, Eva R.; Koskela, Esa; Lonn, Eija; Mappes, Johanna; Mökkönen, Mikael

doi:10.1098/rspb.2017.1896

Cited by 28 publications

(16 citation statements)

References 46 publications

(106 reference statements)

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“…We found a significant drop of the predominant 21-repeat allele frequency in the disease-only genotypes compartment. Instances of STR allele selection in animals have been reported in the 5′ regulatory region of arginine vasopressin 1a receptor and oxytocin receptor loci [30].…”

Section: Discussionmentioning

confidence: 99%

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

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Background: Approximately 2% of the human core promoter short tandem repeats (STRs) reach lengths of ≥6 repeats, which may in part be a result of adaptive evolutionary processes and natural selection. A single-exon transcript of the human nescient helix loop helix 2 (NHLH2) gene is flanked by the longest CA-repeat detected in a human protein-coding gene core promoter (Ensembl transcript ID: ENST00000369506.1). NHLH2 is involved in several biological and pathological pathways, such as motivated exercise, obesity, and diabetes. Methods: The allele and genotype distribution of the NHLH2 CA-repeat were investigated by sequencing in 655 Iranian subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 290) and matched controls (n = 365). The evolutionary trend of the CA-repeat was also studied across vertebrates. Results: The allele range was between 9 and 25 repeats in the NCD cases, and 12 and 24 repeats in the controls. At the frequency of 0.56, the 21-repeat allele was the predominant allele in the controls. While the 21-repeat was also the predominant allele in the NCD patients, we detected significant decline of the frequency (p < 0.0001) and homozygosity (p < 0.006) of this allele in this group. Furthermore, 12 genotypes were detected across 16 patients (5.5% of the entire NCD sample) and not in the controls (disease-only genotypes; p < 0.0003), consisting of at least one extreme allele. The extreme alleles were at 9, 12, 13, 18, and 19 repeats (extreme short end), and 23, 24, and 25 repeats (extreme long end), and their frequencies ranged between 0.001 and 0.04. The frequency of the 21-repeat allele significantly dropped to 0.09 in the disease-only genotype compartment (p <

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Section: Discussionmentioning

confidence: 99%

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

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“…Research on some mammals has recently linked microsatellites located within vasopressin and oxytocin receptor genes to reproductive success and gene expression variation in the brain with evidence for balancing selection maintaining microsatellite length polymorphisms at these loci (Lonn et al, 2017). Evidence linking promoter microsatellites to neuronal and craniofocal development in primates (Namdar‐Aligoodarzi et al., 2015; Ohadi et al., 2015), and reports of selection acting on extreme allele length have also emerged (Watts et al., 2017). However, little is known about the mechanisms by which microsatellites can influence phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Transcribed microsatellite allele lengths are often correlated with gene expression in natural sunflower populations

et al. 2020

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Microsatellites are common in genomes of most eukaryotic species. Due to their high mutability, an adaptive role for microsatellites has been considered. However, little is known concerning the contribution of microsatellites towards phenotypic variation.We used populations of the common sunflower (Helianthus annuus) at two latitudes to quantify the effect of microsatellite allele length on phenotype at the level of gene expression. We conducted a common garden experiment with seed collected from sunflower populations in Kansas and Oklahoma followed by an RNA-Seq experiment on 95 individuals. The effect of microsatellite allele length on gene expression was assessed across 3,325 microsatellites that could be consistently scored. Our study revealed 479 microsatellites at which allele length significantly correlates with gene expression (eSTRs). When irregular allele sizes not conforming to the motif length were removed, the number of eSTRs rose to 2,379. The percentage of variation in gene expression explained by eSTRs ranged from 1%-86% when controlling for population and allele-by-population interaction effects at the 479 eSTRs. Of these eSTRs, 70.4% are in untranslated regions (UTRs). A gene ontology (GO) analysis revealed that eSTRs are significantly enriched for GO terms associated with cis-and transregulatory processes. Our findings suggest that a substantial number of transcribed microsatellites can influence gene expression. K E Y W O R D S gene expression, Helianthus annuus, microsatellite, sunflower | 1705 RANATHUNGE ET Al. S U PP O RTI N G I N FO R M ATI O NAdditional supporting information may be found online in the Supporting Information section.

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“…Recent reports indicate that STR length in uences expression quantitative trait loci (eQTL) associations (32). It should be noted that instances of STR allele selection in animals have been reported in the 5′ regulatory region of arginine vasopressin 1a receptor and oxytocin receptor loci (33).…”

Section: Discussionmentioning

confidence: 99%

Directional Decremental Abundance of (GA)9 and (GA)11 Blocks in Primate Speciation

Khamse

Arabfard

Salesi

et al. 2021

Preprint

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Background: Recent evidence indicates that expansion of a number of short tandem repeats (STRs) may be a result of natural selection. The human neuron-specific genes, RIT2 and GPM6B, contain two of the longest GA-STRs at 11 and 9-repeats, respectively, the length ranges of which are functional, and exceedingly rare repeats at the extreme end of those STRs occur with major human disorders. To examine the evolutionary trend of (GA)11 and (GA)9 blocks, two sets of chromosomal regions (each spanning 10 Mb of genomic DNA) across all chromosomes, were searched for those blocks across rodent and primate orders. We also sequenced the RIT2 and GPM6B STRs in 600 human subjects, consisting of late-onset neurocognitive disorder (n=200), multiple sclerosis (n=100), and controls (n=200). Results: We detected a directional decremental abundance of (GA)11 and (GA)9 blocks, matching the phylogenetic distance of the selected species as follows: mouse>macaque>great apes (p=0.000006). The RIT2 and GPM6B GA-repeats were at strict lengths of 11 and 9-repeats in human, respectively, and were predominantly human-specific in formula. Exception included a 9/11 genotype of the RIT2 GA-STR in an isolate case of multiple sclerosis. Conclusion: We report the first evidence of massive directional trend of STRs linking to speciation. Genes such as RIT2 and GPM6B may be suitable candidates to explore the evolutionary impact of STR blocks.

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Stabilizing selection on microsatellite allele length at arginine vasopressin 1a receptor and oxytocin receptor loci

Cited by 28 publications

References 46 publications

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Transcribed microsatellite allele lengths are often correlated with gene expression in natural sunflower populations

Directional Decremental Abundance of (GA)9 and (GA)11 Blocks in Primate Speciation

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