Demographic History, Adaptation, and NRAP Convergent Evolution at Amino Acid Residue 100 in the World Northernmost Cattle from Siberia.

Native cattle breeds represent an important cultural heritage. They are a reservoir of genetic variation useful for properly responding to agriculture needs in the light of ongoing climate changes. Evolutionary processes that occur in response to extreme environmental conditions could also be better understood using adapted local populations. Herein, different evolutionary histories of the world northernmost native cattle breeds from Russia were investigated. They highlighted Kholmogory as a typical taurine cattle, whereas Yakut cattle separated from European taurines approximately 5,000 years ago and contain numerous ancestral and some novel genetic variants allowing their adaptation to harsh conditions of living above the Polar Circle. Scans for selection signatures pointed to several common gene pathways related to adaptation to harsh climates in both breeds. But genes affected by selection from these pathways were mostly different. A Yakut cattle breed-specific missense mutation in a highly conserved NRAP gene represents a unique example of a young amino acid residue convergent change shared with at least 16 species of hibernating/cold-adapted mammals from six distinct phylogenetic orders. This suggests a convergent evolution event along the mammalian phylogenetic tree and fast fixation in a single isolated cattle population exposed to a harsh climate.

High-density genotyping reveals signatures of selection related to acclimation and economically important traits in 15 local sheep breeds from Russia.

BACKGROUND: Domestication and centuries of selective breeding have changed genomes of sheep breeds to respond to environmental challenges and human needs. The genomes of local breeds, therefore, are valuable sources of genomic variants to be used to understand mechanisms of response to adaptation and artificial selection. As a step toward this we performed a high-density genotyping and comprehensive scans for signatures of selection in the genomes from 15 local sheep breeds reared across Russia. RESULTS: Results demonstrated that the genomes of Russian sheep breeds contain multiple regions under putative selection. More than 50% of these regions matched with intervals identified in previous scans for selective sweeps in sheep genomes. These regions contain well-known candidate genes related to morphology, adaptation, and domestication (e.g., KITLG, KIT, MITF, and MC1R), wool quality and quantity (e.g., DSG@, DSC@, and KRT@), growth and feed intake (e.g., HOXA@, HOXC@, LCORL, NCAPG, LAP3, and CCSER1), reproduction (e.g., CMTM6, HTRA1, GNAQ, UBQLN1, and IFT88), and milk-related traits (e.g., ABCG2, SPP1, ACSS1, and ACSS2). In addition, multiple genes that are putatively related to environmental adaptations were top-ranked in selected intervals (e.g., EGFR, HSPH1, NMUR1, EDNRB, PRL, TSHR, and ADAMTS5). Moreover, we observed that multiple key genes involved in human hereditary sensory and autonomic neuropathies, and genetic disorders accompanied with an inability to feel pain and environmental temperatures, were top-ranked in multiple or individual sheep breeds from Russia pointing to a possible mechanism of adaptation to harsh climatic conditions. CONCLUSIONS: Our work represents the first comprehensive scan for signatures of selection in genomes of local sheep breeds from the Russian Federation of both European and Asian origins. We confirmed that the genomes of Russian sheep contain previously identified signatures of selection, demonstrating the robustness of our integrative approach. Multiple novel signatures of selection were found near genes which could be related to adaptation to the harsh environments of Russia. Our study forms a basis for future work on using Russian sheep genomes to spot specific genetic variants or haplotypes to be used in efforts on developing next-generation highly productive breeds, better suited to diverse Eurasian environments.

Genome-wide association study and scan for signatures of selection point to candidate genes for body temperature maintenance under the cold stress in Siberian cattle populations.

BACKGROUND: Design of new highly productive livestock breeds, well-adapted to local climatic conditions is one of the aims of modern agriculture and breeding. The genetics underlying economically important traits in cattle are widely studied, whereas our knowledge of the genetic mechanisms of adaptation to local environments is still scarce. To address this issue for cold climates we used an integrated approach for detecting genomic intervals related to body temperature maintenance under acute cold stress. Our approach combined genome-wide association studies (GWAS) and scans for signatures of selection applied to a cattle population (Hereford and Kazakh Whiteheaded beef breeds) bred in Siberia. We utilized the GGP HD150K DNA chip containing 139,376 single nucleotide polymorphism markers. RESULTS: We detected a single candidate region on cattle chromosome (BTA)15 overlapping between the GWAS results and the results of scans for selective sweeps. This region contains two genes, MSANTD4 and GRIA4. Both genes are functional candidates to contribute to the cold-stress resistance phenotype, due to their indirect involvement in the cold shock response (MSANTD4) and body thermoregulation (GRIA4). CONCLUSIONS: Our results point to a novel region on BTA15 which is a candidate region associated with the body temperature maintenance phenotype in Siberian cattle. The results of our research and the follow up studies might be used for the development of cattle breeds better adapted to cold climates of the Russian Federation and other Northern countries with similar climates.

A database of human genes and a gene network involved in response to tick-borne encephalitis virus infection.

BACKGROUND: Tick-borne encephalitis is caused by the neurotropic, positive-sense RNA virus, tick-borne encephalitis virus (TBEV). TBEV infection can lead to a variety of clinical manifestations ranging from slight fever to severe neurological illness. Very little is known about genetic factors predisposing to severe forms of disease caused by TBEV. The aims of the study were to compile a catalog of human genes involved in response to TBEV infection and to rank genes from the catalog based on the number of neighbors in the network of pairwise interactions involving these genes and TBEV RNA or proteins. RESULTS: Based on manual review and curation of scientific publications a catalog comprising 140 human genes involved in response to TBEV infection was developed. To provide access to data on all genes, the TBEVhostDB web resource ( http://icg.nsc.ru/TBEVHostDB/ ) was created. We reconstructed a network formed by pairwise interactions between TBEV virion itself, viral RNA and viral proteins and 140 genes/proteins from TBEVHostDB. Genes were ranked according to the number of interactions in the network. Two genes/proteins (CCR5 and IFNAR1) that had maximal number of interactions were revealed. It was found that the subnetworks formed by CCR5 and IFNAR1 and their neighbors were a fragments of two key pathways functioning during the course of tick-borne encephalitis: (1) the attenuation of interferon-I signaling pathway by the TBEV NS5 protein that targeted peptidase D; (2) proinflammation and tissue damage pathway triggered by chemokine receptor CCR5 interacting with CD4, CCL3, CCL4, CCL2. Among nine genes associated with severe forms of TBEV infection, three genes/proteins (CCR5, IL10, ARID1B) were found to have protein-protein interactions within the network, and two genes/proteins (IFNL3 and the IL10, that was just mentioned) were up- or down-regulated in response to TBEV infection. Based on this finding, potential mechanisms for participation of CCR5, IL10, ARID1B, and IFNL3 in the host response to TBEV infection were suggested. CONCLUSIONS: A database comprising 140 human genes involved in response to TBEV infection was compiled and the TBEVHostDB web resource, providing access to all genes was created. This is the first effort of integrating and unifying data on genetic factors that may predispose to severe forms of diseases caused by TBEV. The TBEVHostDB could potentially be used for assessment of risk factors for severe forms of tick-borne encephalitis and for the design of personalized pharmacological strategies for the treatment of TBEV infection.

A compendium and functional characterization of mammalian genes involved in adaptation to Arctic or Antarctic environments.

BACKGROUND: Many mammals are well adapted to surviving in extremely cold environments. These species have likely accumulated genetic changes that help them efficiently cope with low temperatures. It is not known whether the same genes related to cold adaptation in one species would be under selection in another species. The aims of this study therefore were: to create a compendium of mammalian genes related to adaptations to a low temperature environment; to identify genes related to cold tolerance that have been subjected to independent positive selection in several species; to determine promising candidate genes/pathways/organs for further empirical research on cold adaptation in mammals. RESULTS: After a search for publications containing keywords: "whole genome", "transcriptome or exome sequencing data", and "genome-wide genotyping array data" authors looked for information related to genetic signatures ascribable to positive selection in Arctic or Antarctic mammalian species. Publications related to Human, Arctic fox, Yakut horse, Mammoth, Polar bear, and Minke whale were chosen. The compendium of genes that potentially underwent positive selection in >1 of these six species consisted of 416 genes. Twelve of them showed traces of positive selection in three species. Gene ontology term enrichment analysis of 416 genes from the compendium has revealed 13 terms relevant to the scope of this study. We found that enriched terms were relevant to three major groups: terms associated with collagen proteins and the extracellular matrix; terms associated with the anatomy and physiology of cilium; terms associated with docking. We further revealed that genes from compendium were over-represented in the lists of genes expressed in the lung and liver. CONCLUSIONS: A compendium combining mammalian genes involved in adaptation to cold environment was designed, based on the intersection of positively selected genes from six Arctic and Antarctic species. The compendium contained 416 genes that have been positively selected in at least two species. However, we did not reveal any positively selected genes that would be related to cold adaptation in all species from our list. But, our work points to several strong candidate genes involved in mechanisms and biochemical pathways related to cold adaptation response in different species.

A Multibreed Genome-Wide Association Study for Cattle Leukocyte Telomere Length.

Telomeres are terminal DNA regions of chromosomes that prevent chromosomal fusion and degradation during cell division. In cattle, leukocyte telomere length (LTL) is associated with longevity, productive lifespan, and disease susceptibility. However, the genetic basis of LTL in this species is less studied than in humans. In this study, we utilized the whole-genome resequencing data of 239 animals from 17 cattle breeds for computational leukocyte telomere length estimation and subsequent genome-wide association study of LTL. As a result, we identified 42 significant SNPs, of which eight were found in seven genes (EXOC6B, PTPRD, RPS6KC1, NSL1, AGBL1, ENSBTAG00000052188, and GPC1) when using covariates for two major breed groups (Turano-Mongolian and European). Association analysis with covariates for breed effect detected 63 SNPs, including 13 in five genes (EXOC6B, PTPRD, RPS6KC1, ENSBTAG00000040318, and NELL1). The PTPRD gene, demonstrating the top signal in analysis with breed effect, was previously associated with leukocyte telomere length in cattle and likely is involved in the mechanism of alternative lengthening of telomeres. The single nucleotide variants found could be tested for marker-assisted selection to improve telomere-length-associated traits.

Copy Number Variants in Two Northernmost Cattle Breeds Are Related to Their Adaptive Phenotypes.

Copy number variations (CNVs) are genomic structural variants with potential functional and evolutionary effects on phenotypes. In this study, we report the identification and characterization of CNVs from the whole-genome resequencing data of two northernmost cattle breeds from Russia: the Yakut and Kholmogory cattle and their phylogenetically most related breeds, Hanwoo and Holstein, respectively. Comparisons of the CNV regions (CNVRs) among the breeds led to the identification of breed-specific CNVRs shared by cold-adapted Kholmogory and Yakut cattle. An investigation of their overlap with genes, regulatory domains, conserved non-coding elements (CNEs), enhancers, and quantitative trait loci (QTLs) was performed to further explore breed-specific biology and adaptations. We found CNVRs enriched for gene ontology terms related to adaptation to environments in both the Kholmogory and Yakut breeds and related to thermoregulation specifically in Yakut cattle. Interestingly, the latter has also been supported when exploring the enrichment of breed-specific CNVRs in the regulatory domains and enhancers, CNEs, and QTLs implying the potential contribution of CNVR to the Yakut and Kholmogory cattle breeds' adaptation to a harsh environment.

Genotyping and Whole-Genome Resequencing of Welsh Sheep Breeds Reveal Candidate Genes and Variants for Adaptation to Local Environment and Socioeconomic Traits.

BACKGROUND: Advances in genetic tools applied to livestock breeding has prompted research into the previously neglected breeds adapted to harsh local environments. One such group is the Welsh mountain sheep breeds, which can be farmed at altitudes of 300 m above sea level but are considered to have a low productive value because of their poor wool quality and small carcass size. This is contrary to the lowland breeds which are more suited to wool and meat production qualities, but do not fare well on upland pasture. Herein, medium-density genotyping data from 317 individuals representing 15 Welsh sheep breeds were used alongside the whole-genome resequencing data of 14 breeds from the same set to scan for the signatures of selection and candidate genetic variants using haplotype- and SNP-based approaches. RESULTS: Haplotype-based selection scan performed on the genotyping data pointed to a strong selection in the regions of GBA3, PPARGC1A, APOB, and PPP1R16B genes in the upland breeds, and RNF24, PANK2, and MUC15 in the lowland breeds. SNP-based selection scan performed on the resequencing data pointed to the missense mutations under putative selection relating to a local adaptation in the upland breeds with functions such as angiogenesis (VASH1), anti-oxidation (RWDD1), cell stress (HSPA5), membrane transport (ABCA13 and SLC22A7), and insulin signaling (PTPN1 and GIGFY1). By contrast, genes containing candidate missense mutations in the lowland breeds are related to cell cycle (CDK5RAP2), cell adhesion (CDHR3), and coat color (MC1R). CONCLUSION: We found new variants in genes with potentially functional consequences to the adaptation of local sheep to their environments in Wales. Knowledge of these variations is important for improving the adaptative qualities of UK and world sheep breeds through a marker-assisted selection.

Searching for Signatures of Cold Climate Adaptation in TRPM8 Gene in Populations of East Asian Ancestry.

Dispersal of Homo sapiens across the globe during the last 200,000 years was accompanied by adaptation to local climatic conditions, with severe winter temperatures being probably one of the most significant selective forces. The TRPM8 gene codes for a cold-sensing ion channel, and adaptation to low temperatures is the major determinant of its molecular evolution. Here, our aim was to search for signatures of cold climate adaptation in TRPM8 gene using a combined data set of 19 populations of East Asian ancestry from the 1000 Genomes Project and Human Genome Diversity Project. As a result, out of a total of 60 markers under study, none showed significant association with the average winter temperatures at the locations of the studied populations considering the multiple testing thresholds. This might suggest that the principal mode of TRPM8 evolution may be different from widespread models, where adaptive alleles are additive, dominant or recessive, at least in populations with the predominant East Asian component. For example, evolution by means of selectively preferable epistatic interactions among amino acids may have taken place. Despite the lack of strong signals of association, however, a very promising single nucleotide polymorphism (SNP) was found. The SNP rs7577262 is considered the best candidate based on its allelic correlations with winter temperatures, signatures of selective sweep and physiological evidences. The second top SNP, rs17862920, may participate in adaptation as well. Additionally, to assist in interpreting the nominal associations, the other markers reached, we performed SNP prioritization based on functional evidences found in literature and on evolutionary conservativeness.

Exome-wide search and functional annotation of genes associated in patients with severe tick-borne encephalitis in a Russian population.

BACKGROUND: Tick-borne encephalitis (TBE) is a viral infectious disease caused by tick-borne encephalitis virus (TBEV). TBEV infection is responsible for a variety of clinical manifestations ranging from mild fever to severe neurological illness. Genetic factors involved in the host response to TBEV that may potentially play a role in the severity of the disease are still poorly understood. In this study, using whole-exome sequencing, we aimed to identify genetic variants and genes associated with severe forms of TBE as well as biological pathways through which the identified variants may influence the severity of the disease. RESULTS: Whole-exome sequencing data analysis was performed on 22 Russian patients with severe forms of TBE and 17 Russian individuals from the control group. We identified 2407 candidate genes harboring rare, potentially pathogenic variants in exomes of patients with TBE and not containing any rare, potentially pathogenic variants in exomes of individuals from the control group. According to DAVID tool, this set of 2407 genes was enriched with genes involved in extracellular matrix proteoglycans pathway and genes encoding proteins located at the cell periphery. A total of 154 genes/proteins from these functional groups have been shown to be involved in protein-protein interactions (PPIs) with the known candidate genes/proteins extracted from TBEVHostDB database. By ranking these genes according to the number of rare harmful minor alleles, we identified two genes (MSR1 and LMO7), harboring five minor alleles, and three genes (FLNA, PALLD, PKD1) harboring four minor alleles. When considering genes harboring genetic variants associated with severe forms of TBE at the suggestive P-value < 0.01, 46 genes containing harmful variants were identified. Out of these 46 genes, eight (MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) were additionally found among genes containing rare pathogenic variants identified in patients with TBE; and five genes (WDFY4, ALK, MAP4, BNIPL, EPPK1) were found to encode proteins that are involved in PPIs with proteins encoded by genes from TBEVHostDB. Three genes out of five (MAP4, EPPK1, ALK) were found to encode proteins located at cell periphery. CONCLUSIONS: Whole-exome sequencing followed by systems biology approach enabled to identify eight candidate genes (MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) that can potentially determine predisposition to severe forms of TBE. Analyses of the genetic risk factors for severe forms of TBE revealed a significant enrichment with genes controlling extracellular matrix proteoglycans pathway as well as genes encoding components of cell periphery.

A matrix metalloproteinase 9 (MMP9) gene single nucleotide polymorphism is associated with predisposition to tick-borne encephalitis virus-induced severe central nervous system disease.

The progression of infectious diseases depends on causative agents, the environment and the host's genetic susceptibility. To date, human genetic susceptibility to tick-borne encephalitis (TBE) virus-induced disease has not been sufficiently studied. We have combined whole-exome sequencing with a candidate gene approach to identify genes that are involved in the development of predisposition to TBE in a Russian population. Initially, six exomes from TBE patients with severe central nervous system (CNS) disease and seven exomes from control individuals were sequenced. Despite the small sample size, two nonsynonymous single nucleotide polymorphisms (SNPs) were significantly associated with TBE virus-induced severe CNS disease. One of these SNPs is rs6558394 (G/A, Pro422Leu) in the scribbled planar cell polarity protein (SCRIB) gene and the other SNP is rs17576 (A/G, Gln279Arg) in the matrix metalloproteinase 9 (MMP9) gene. Subsequently, these SNPs were genotyped in DNA samples of 150 non-immunized TBE patients with different clinical forms of the disease from two cities and 228 control randomly selected samples from the same populations. There were no statistically significant differences in genotype and allele frequencies between the case and control groups for rs6558394. However, the frequency of the rs17576 G allele was significantly higher in TBE patients with severe CNS diseases such as meningo-encephalitis (43.5%) when compared with TBE patients with milder meningitis (26.3%; P = 0.01), as well as with the population control group (32.5%; P = 0.042). The results suggest that the MMP9 gene may affect genetic predisposition to TBE in a Russian population.

Genetic basis of olfactory cognition: extremely high level of DNA sequence polymorphism in promoter regions of the human olfactory receptor genes revealed using the 1000 Genomes Project dataset.

The molecular mechanism of olfactory cognition is very complicated. Olfactory cognition is initiated by olfactory receptor proteins (odorant receptors), which are activated by olfactory stimuli (ligands). Olfactory receptors are the initial player in the signal transduction cascade producing a nerve impulse, which is transmitted to the brain. The sensitivity to a particular ligand depends on the expression level of multiple proteins involved in the process of olfactory cognition: olfactory receptor proteins, proteins that participate in signal transduction cascade, etc. The expression level of each gene is controlled by its regulatory regions, and especially, by the promoter [a region of DNA about 100-1000 base pairs long located upstream of the transcription start site (TSS)]. We analyzed single nucleotide polymorphisms using human whole-genome data from the 1000 Genomes Project and revealed an extremely high level of single nucleotide polymorphisms in promoter regions of olfactory receptor genes and HLA genes. We hypothesized that the high level of polymorphisms in olfactory receptor promoters was responsible for the diversity in regulatory mechanisms controlling the expression levels of olfactory receptor proteins. Such diversity of regulatory mechanisms may cause the great variability of olfactory cognition of numerous environmental olfactory stimuli perceived by human beings (air pollutants, human body odors, odors in culinary etc.). In turn, this variability may provide a wide range of emotional and behavioral reactions related to the vast variety of olfactory stimuli.