Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.

Alteration in gene expression levels underlies many of the phenotypic differences across species. Because of their highly mutable nature, proximity to the +1 transcription start site (TSS), and the emerging evidence of functional impact on gene expression, core promoter short tandem repeats (STRs) may be considered an ideal source of variation across species. In a genome-scale analysis of the entire Homo sapiens protein-coding genes, we have previously identified core promoters with at least one STR of ≥ 6-repeats, with possible selective advantage in this species. In the current study, we performed reverse analysis of the entire Homo sapiens orthologous genes in mouse in the Ensembl database, in order to identify conserved STRs that have shrunk as an evolutionary advantage to humans. Two protocols were used to minimize ascertainment bias. Firstly, two species sharing a more recent ancestor with Homo sapiens (i.e. Pan troglodytes and Gorilla gorilla gorilla) were also included in the study. Secondly, four non-primate species encompassing the major orders across Mammals, including Scandentia, Laurasiatheria, Afrotheria, and Xenarthra were analyzed as out-groups. We introduce STR evolutionary events specifically identical in primates (i.e. Homo sapiens, Pan troglodytes, and Gorilla gorilla gorilla) vs. non-primate out-groups. The average frequency of the identically shared STR motifs across those primates ranged between 0.00005 and 0.06. The identified genes are involved in important evolutionary and developmental processes, such as normal craniofacial development (TFAP2B), regulation of cell shape (PALMD), learning and long-term memory (RGS14), nervous system development (GFRA2), embryonic limb morphogenesis (PBX2), and forebrain development (APAF1). We provide evidence of core promoter STRs as evolutionary switch codes for primate speciation, and the first instance of identity-by-descent for those motifs at the interspecies level.

Neurological disorders include a wide variety of mostly multifactorial diseases related to the development, survival, and function of the neuron cells. Single-nucleotide polymorphisms (SNPs) have been extensively studied in neurological disorders, and in a number of instances have been reproducibly linked to disease as risk factors. The RIT2 gene has been recently shown to be associated with a number of neurological disorders, such as Parkinson's disease (PD) and autism. In the study reported here, we investigated the association of the rs12456492 and rs16976358 SNPs of the RIT2 gene with PD, essential tremor (ET), autism, schizophrenia (SCZ), and bipolar disorder (BPD; total of 2290 patients), and 1000 controls, by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant association was observed between rs12456492 and two disorders, PD and ET, whereas rs16976358 was found to be associated with autism, SCZ, and BPD. Our findings are indicative of differential association between the RIT2 SNPs and different neurological disorders.

BackgroundDespite their vast biological implication, the relevance of short tandem repeats (STRs)/microsatellites to the protein-coding gene translation initiation sites (TISs) remains largely unknown.MethodsWe performed an Ensembl-based comparative genomics study of all annotated orthologous TIS-flanking sequences in human and 46 other species across vertebrates, on the genomic DNA and cDNA platforms (755,956 TISs), aimed at identifying human-specific STRs in this interval. The collected data were used to examine the hypothesis of a link between STRs and TISs. BLAST was used to compare the initial five amino acids (excluding the initial methionine), codons of which were flanked by STRs in human, with the initial five amino acids of all annotated proteins for the orthologous genes in other vertebrates (total of 5,314,979 pair-wise TIS comparisons on the genomic DNA and cDNA platforms) in order to compare the number of events in which human-specific and non-specific STRs occurred with homologous and non-homologous TISs (i.e., ≥ 50% and < 50% similarity of the five amino acids).ResultsWe detected differential distribution of the human-specific STRs in comparison to the overall distribution of STRs on the genomic DNA and cDNA platforms (Mann Whitney U test p = 1.4 × 10−11 and p < 7.9 × 10−11, respectively). We also found excess occurrence of non-homologous TISs with human-specific STRs and excess occurrence of homologous TISs with non-specific STRs on both platforms (p < 0.00001).ConclusionWe propose a link between STRs and TIS selection, based on the differential co-occurrence rate of human-specific STRs with non-homologous TISs and non-specific STRs with homologous TISs.Electronic supplementary materialThe online version of this article (10.1186/s40246-018-0181-3) contains supplementary material, which is available to authorized users.

Adaptive evolution may be linked with the genomic distribution and function of short tandem repeats (STRs). Proximity of the core promoter STRs to the +1 transcription start site (TSS), and their mutable nature are characteristics that highlight those STRs as a novel source of interspecies variation. The PAXBP1 gene (alternatively known as GCFC1) core promoter contains the longest STR identified in a Homo sapiens gene core promoter. Indeed, this core promoter is a stretch of four consecutive CT-STRs. In the current study, we used the Ensembl, NCBI, and UCSC databases to analyze the evolutionary trend and functional implication of this CT-STR complex in six major lineages across vertebrates, including primates, non-primate mammals, birds, reptiles, amphibians, and fish. We observed exceptional expansion (≥4-repeats) and conservation of this CT-STR complex across primates, except prosimians, Microcebus murinus and Otolemur garnettii (Fisher exact P<4.1×10(-7)). H. sapiens has the most complex STR formula, and longest repeats. Macaca mulatta and Callithrix jacchus monkeys have the simplest STR formulas, and shortest repeat numbers. CT≥4-repeats were not detected in non-primate lineages. Different length alleles across the PAXBP1 core promoter CT-STRs significantly altered gene expression in vitro (P<0.001, t-test). PAXBP1 has a crucial role in craniofacial development, myogenesis, and spine morphogenesis, properties that have been diverged between primates and non-primates. To our knowledge, this is the first instance of expansion and conservation of a STR complex co-occurring specifically with the primate lineage.