A 175 Million Year History of T Cell Regulatory Molecules Reveals Widespread Selection, with Adaptive Evolution of Disease Alleles

Forni, Diego; Cagliani, Rachele; Colleoni, M.; Riva, Stefania; Biasin, Mara; Filippi, Giulia; Gioia, Luca De; Gnudi, Federica; Comi, Giacomo P.; Bresolin, Nereo; Clerici, Mario; Sironi, Manuela

doi:10.1016/j.immuni.2013.04.008

Cited by 29 publications

(30 citation statements)

References 62 publications

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“…Specifically, DIND values were calculated for all SNPs using a constant number of 40 flanking variants (20 up-and downstream). The distributions of DIND-DAF pairs for CEPH and CHB + JPT were binned in DAF intervals (100 classes) and for each class the 95 th percentile was calculated [74]. As suggested previously [27], for values of iπ D = 0 we set the DIND value to the maximum obtained over the whole dataset plus 20.…”

Section: Hgdp-ceph Data and Statistical Analysismentioning

confidence: 99%

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

et al. 2014

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Background: The temporal coordination of biological processes into daily cycles is a common feature of most living organisms. In humans, disruption of circadian rhythms is commonly observed in psychiatric diseases, including schizophrenia, bipolar disorder, depression and autism. Light therapy is the most effective treatment for seasonal affective disorder and circadian-related treatments sustain antidepressant response in bipolar disorder patients. Day/night cycles represent a major circadian synchronizing signal and vary widely with latitude. Results: We apply a geographically explicit model to show that out-of-Africa migration, which led humans to occupy a wide latitudinal area, affected the evolutionary history of circadian regulatory genes. The SNPs we identify using this model display consistent signals of natural selection using tests based on population genetic differentiation and haplotype homozygosity. Signals of natural selection driven by annual photoperiod variation are detected for schizophrenia, bipolar disorder, and restless leg syndrome risk variants, in line with the circadian component of these conditions. Conclusions: Our results suggest that human populations adapted to life at different latitudes by tuning their circadian clock systems. This process also involves risk variants for neuropsychiatric conditions, suggesting possible genetic modulators for chronotherapies and candidates for interaction analysis with photoperiod-related environmental variables, such as season of birth, country of residence, shift-work or lifestyle habits.

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Section: Hgdp-ceph Data and Statistical Analysismentioning

confidence: 99%

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

et al. 2014

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“…As mentioned above, the combined use of distinct tests is expected to afford higher resolution in detecting the causal variant underlying the adaptive phenotype and to reduce the rate of false positive signals. [29][30][31] As for DH, which has more power than the original Fay and Wu's H statistic, it was used as a confirmatory test. 34 This choice was motivated by the difficulty of assessing statistical significance in sliding-window analyses, as multiple non-independent tests are performed.…”

Section: Discussionmentioning

confidence: 99%

“…[29][30][31] We applied the DIND (Derived Intra-allelic Nucleotide Diversity) test, which is powerful in most derived allele frequency (DAF) ranges and less sensitive than iHS (Integrated Haplotype Score) to low genotype quality or low coverage (i.e. it is well suited for the 1000G data).…”

Section: Non-coding Regulatory Variants Represent Targets Of Positivementioning

confidence: 99%

“…26,64,65 The pairwise F ST and the DIND (Derived Intra-allelic Nucleotide Diversity) test were calculated for all SNPs mapping to ADAR, ADARB1 and ADARB2, as well as for SNPs mapping to a control set of »1,000 genes; these latter were used as a reference, as previously described. [30][31][32]66 F ST values are not independent from allele frequencies, so we binned variants based on their minor allele frequency (MAF, 50 classes) and calculated F ST empirical distributions for each MAF class. The same procedure was applied for the DIND test; thus, we calculated statistical significance by obtaining an empirical distribution of DIND values for variants located within control genes; in particular, the DIND test was calculated using a constant number of 20 upstream and downstream flanking variants, as previously described.…”

Section: Population Genetics Analysesmentioning

confidence: 99%

“…The same procedure was applied for the DIND test; thus, we calculated statistical significance by obtaining an empirical distribution of DIND values for variants located within control genes; in particular, the DIND test was calculated using a constant number of 20 upstream and downstream flanking variants, as previously described. 30,31 DIND values for YRI, CEU and AS were binned in derived allele frequency (DAF) intervals (100 classes) and for each class the distributions were calculated. As suggested, for values of ip D =0 we set the DIND value to the maximum obtained over the whole dataset plus 20.…”

Section: Population Genetics Analysesmentioning

confidence: 99%

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Diverse selective regimes shape genetic diversity atADARgenes and at their coding targets

et al. 2015

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A-to-I RNA editing operated by ADAR enzymes is extremely common in mammals. Several editing events in coding regions have pivotal physiological roles and affect protein sequence (recoding events) or function. We analyzed the evolutionary history of the 3 ADAR family genes and of their coding targets. Evolutionary analysis indicated that ADAR evolved adaptively in primates, with the strongest selection in the unique N-terminal domain of the interferoninducible isoform. Positively selected residues in the human lineage were also detected in the ADAR deaminase domain and in the RNA binding domains of ADARB1 and ADARB2. During the recent history of human populations distinct variants in the 3 genes increased in frequency as a result of local selective pressures. Most selected variants are located within regulatory regions and some are in linkage disequilibrium with eQTLs in monocytes. Finally, analysis of conservation scores of coding editing sites indicated that editing events are counter-selected within regions that are poorly tolerant to change. Nevertheless, a minority of recoding events occurs at highly conserved positions and possibly represents the functional fraction. These events are enriched in pathways related to HIV-1 infection and to epidermis/hair development. Thus, both ADAR genes and their targets evolved under variable selective regimes, including purifying and positive selection. Pressures related to immune response likely represented major drivers of evolution for ADAR genes. As for their coding targets, we suggest that most editing events are slightly deleterious, although a minority may be beneficial and contribute to antiviral response and skin homeostasis.

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Evolutionary history of type II transmembrane serine proteases involved in viral priming

2022

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Type II transmembrane serine proteases (TTSPs) are a family of trypsin-like membrane-anchored serine proteases that play key roles in the regulation of some crucial processes in physiological conditions, including cardiac function, digestion, cellular iron homeostasis, epidermal differentiation, and immune responses. However, some of them, in particular TTSPs expressed in the human airways, were identified as host factors that promote the proteolytic activation and spread of respiratory viruses such as influenza virus, human metapneumovirus, and coronaviruses, including SARS-CoV-2. Given their involvement in viral priming, we hypothesized that members of the TTSP family may represent targets of positive selection, possibly as the result of virus-driven pressure. Thus, we investigated the evolutionary history of sixteen TTSP genes in mammals. Evolutionary analyses indicate that most of the TTSP genes that have a verified role in viral proteolytic activation present signals of pervasive positive selection, suggesting that viral infections represent a selective pressure driving the evolution of these proteases. We also evaluated genetic diversity in human populations and we identified targets of balancing selection in TMPRSS2 and TMPRSS4 . This scenario may be the result of an ancestral and still ongoing host–pathogen arms race. Overall, our results provide evolutionary information about candidate functional sites and polymorphic positions in TTSP genes. Supplementary Information The online version contains supplementary material available at 10.1007/s00439-022-02435-y.

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A 175 Million Year History of T Cell Regulatory Molecules Reveals Widespread Selection, with Adaptive Evolution of Disease Alleles

Cited by 29 publications

References 62 publications

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

Diverse selective regimes shape genetic diversity atADARgenes and at their coding targets

Evolutionary history of type II transmembrane serine proteases involved in viral priming

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