scispace - formally typeset
Open accessJournal ArticleDOI: 10.1016/J.AJHG.2021.01.013

Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation

04 Mar 2021-American Journal of Human Genetics (Elsevier)-Vol. 108, Iss: 3, pp 446-457
Abstract: The protein α-actinin-3 expressed in fast-twitch skeletal muscle fiber is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in ACTN3 (R577X). The prevalence of the 577X allele increased as modern humans moved to colder climates, suggesting a link between α-actinin-3 deficiency and improved cold tolerance. Here, we show that humans lacking α-actinin-3 (XX) are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. Muscles of XX individuals displayed a shift toward more slow-twitch isoforms of myosin heavy chain (MyHC) and sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal muscle activation resulting in increased tone rather than overt shivering. Experiments on Actn3 knockout mice showed no alterations in brown adipose tissue (BAT) properties that could explain the improved cold tolerance in XX individuals. Thus, this study provides a mechanism for the positive selection of the ACTN3 X-allele in cold climates and supports a key thermogenic role of skeletal muscle during cold exposure in humans.

... read more

Topics: Skeletal muscle (60%), Myosin (56%), Heat generation (53%) ... read more

7 results found

Journal ArticleDOI: 10.1016/J.CYTO.2021.155510
03 Apr 2021-Cytokine
Abstract: A poor outcome of whole-body hypothermia often results from a late complication, rather than from acute effects of hypothermia. A low body (cell) temperature or the increase in the concentrations of the stress hormones cortisol, epinephrine, and norepinephrine in response to acute cold stress have been proposed as potent proinflammatory cytokine suppressant. In the current study, we tested the hypothesis that the recovery of body temperature from a whole-body intermittent cold-water immersion (CWI, at 13–14 °C for a total 170 min) is associated with a delayed response of proinflammatory cytokines in young healthy men. Our results revealed a delay in the increase in the proinflammatory interleukin 6 and interleukin 1β cytokines after the CWI, which paralleled the changes in cortisol, epinephrine, norepinephrine, and body temperature. CWI decreased tumor necrosis factor α (TNF-α) immediately and 1 h after the CWI. Although TNF-α had recovered to the pre-immersion level at 2 h after CWI, its natural circadian cycle kinetics was disrupted until 12 h after the CWI. Furthermore, we showed that CWI strongly modified the white blood cell counts, with changes reaching a peak between 1 and 2 h after the CWI.

... read more

Topics: Proinflammatory cytokine (56%), Hypothermia (51%)

2 Citations

Open accessJournal ArticleDOI: 10.1080/02656736.2021.1915504
Abstract: Background: One of the most challenging environmental extremes is immersion in cold/icy water, and consequent common assumption is that even a brief exposure to cold can lead to cold-related illnes...

... read more

1 Citations

Open accessJournal ArticleDOI: 10.1093/MOLBEV/MSAB243
Michal Szpak1, Stephan C. Collins2, Yan Li, Xiao Liu3  +8 moreInstitutions (3)
Abstract: A nonsense allele at rs1343879 in human MAGEE2 on chromosome X has previously been reported as a strong candidate for positive selection in East Asia. This premature stop codon causing ∼80% protein truncation is characterized by a striking geographical pattern of high population differentiation: common in Asia and the Americas (up to 84% in the 1000 Genomes Project East Asians) but rare elsewhere. Here, we generated a Magee2 mouse knockout mimicking the human loss-of-function mutation to study its functional consequences. The Magee2 null mice did not exhibit gross abnormalities apart from enlarged brain structures (13% increased total brain area, P = 0.0022) in hemizygous males. The area of the granular retrosplenial cortex responsible for memory, navigation and spatial information processing was the most severely affected, exhibiting an enlargement of 34% (P = 3.4x10-6). The brain size in homozygous females showed the opposite trend of reduced brain size, although this did not reach statistical significance. With these insights, we performed human association analyses between brain size measurements and rs1343879 genotypes in 141 Chinese volunteers with brain MRI scans, replicating the sexual dimorphism seen in the knockout mouse model. The derived stop gain allele was significantly associated with a larger volume of grey matter in males (P = 0.00094), and smaller volumes of grey (P = 0.00021) and white (P = 0.0015) matter in females. It is unclear whether or not the observed neuroanatomical phenotypes affect behaviour or cognition, but it might have been the driving force underlying the positive selection in humans.

... read more

Topics: Brain size (55%), Sexual dimorphism (52%), Allele (52%) ... read more

Book ChapterDOI: 10.1007/978-3-030-89708-6_7
D. L. Spivak1, Andrei Zhekalov2, Vladislav Nyrov3, Pavel Shapovalov2  +2 moreInstitutions (4)
26 Oct 2021-
Abstract: Present-day state of the theory of genetic foundations of creative performance, primarily at the level of the dopaminergic, serotoninergic, and noradrenergic systems, as well as neuregulin 1 gene, arginine vasopressin receptor, and angiotensinogene, is briefly reviewed. Basic results of a pilot experiment, focused upon four candidate genes for inclusion into creativity studies, namely neurotrophic factor gene (BDNF), α-actinin-3 protein encoding gene (ACTN3), angiotensin-converting enzyme 1 (ACE1), and serotonin-2A receptor gene (5HTR2A), are presented. Strong correlations between high level of creativity, both verbal and figural, and both Val/Val BDNF genotype, and RR ACTN3 genotype, are demonstrated, along with its somewhat weaker correlation with II ACE genotype. Taking into account levels of activation of basic psychological defense mechanisms and stress coping strategies, proper for 22 practically normal Arctic dwellers, who were examined in the framework of our experiment, allowed to link these correlations to optimal adaptation abilities, and to prolonged life expectancy. Basing upon this result, plausibility of discerning between two facets of creativity, one being adaptive, another being non-adaptive, is discussed, the former concerned with primarily coping with life stress, the latter providing self-actualization. Interrelation between the inherited abilities and the acquired ones, forming subject matter of correspondingly genetic and creativity studies, is regarded as a representation of basic dichotomy between nature and culture.

... read more

Open accessJournal ArticleDOI: 10.3389/FGENE.2021.756802
Bonan Dong1, Qiuyan Li1, Tingting Zhang1, Xiao Liang1  +4 moreInstitutions (1)
Abstract: Musculoskeletal performance is a complex trait influenced by environmental and genetic factors, and it has different manifestations in different populations. Heilongjiang province, located in northern China, is a multi-ethnic region with human cultures dating back to the Paleolithic Age. The Daur, Hezhen, Ewenki, Mongolian and Manchu ethnic groups in Heilongjiang province may have strong physical fitness to a certain extent. Based on the genetic characteristics of significant correlation between some important genes and skeletal muscle function, this study selected 23 SNPs of skeletal muscle strength-related genes and analyzed the distribution of these loci and genetic diversity in the five ethnic groups. Use Haploview (version 4.1) software to calculate the chi-square and the Hardy-Weinberg equilibrium to assess the difference between the two ethnic groups. Use R (version 4.0.2) software to perform principal component analysis of different ethnic groups. Use MEGA (version 7.0) software to construct the phylogenetic tree of different ethnic groups. Use POPGENE (version 1.32) software to calculate the heterozygosity and the FST values of 23 SNPs. Use Arlequin (version software to analyze molecular variance (AMOVA) among 31 populations. The results showed that there was haplotype diversity of VDR, angiotensin-converting enzyme, ACTN3, EPO and IGF1 genes in the five ethnic groups, and there were genetic differences in the distribution of these genes in the five ethnic groups. Among them, the average gene heterozygosity (AVE_HET) of the 23 SNPs in the five populations was 0.398. The FST values of the 23 SNPs among the five ethnic groups varied from 0.0011 to 0.0137. According to the principal component analysis, the genetic distance of Daur, Mongolian and Ewenki is relatively close. According to the phylogenetic tree, the five ethnic groups are clustered together with the Asian population. These data will enrich existing genetic information of ethnic minorities.

... read more

Topics: Haploview (52%), Population (52%), Genetic diversity (52%) ... read more


56 results found

Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTP352
Heng Li1, Bob Handsaker2, Alec Wysoker2, T. J. Fennell2  +5 moreInstitutions (4)
01 Aug 2009-Bioinformatics
Abstract: Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: Contact: [email protected]

... read more

Topics: Variant Call Format (62%), Stockholm format (61%), FASTQ format (56%) ... read more

35,747 Citations

Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTS635
01 Jan 2013-Bioinformatics
Abstract: Motivation Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. Results To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. Availability and implementation STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from

... read more

Topics: MRNA Sequencing (57%)

20,172 Citations

Open accessJournal ArticleDOI: 10.1093/NAR/GKV007
Matthew E. Ritchie1, Belinda Phipson2, Di Wu3, Yifang Hu1  +4 moreInstitutions (5)
Abstract: limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.

... read more

Topics: Microarray databases (61%), Bioconductor (51%)

13,819 Citations

Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTU638
15 Jan 2015-Bioinformatics
Abstract: Motivation: A large choice of tools exists for many standard tasks in the analysis of high-throughput sequencing (HTS) data. However, once a project deviates from standard workflows, custom scripts are needed. Results: We present HTSeq, a Python library to facilitate the rapid development of such scripts. HTSeq offers parsers for many common data formats in HTS projects, as well as classes to represent data, such as genomic coordinates, sequences, sequencing reads, alignments, gene model information and variant calls, and provides data structures that allow for querying via genomic coordinates. We also present htseq-count, a tool developed with HTSeq that preprocesses RNA-Seq data for differential expression analysis by counting the overlap of reads with genes. Availability and implementation: HTSeq is released as an opensource software under the GNU General Public Licence and available from or from the Python Package Index at Contact:

... read more

11,833 Citations

Open accessJournal ArticleDOI: 10.1093/NAR/GKY1106
Abstract: The PRoteomics IDEntifications (PRIDE) database ( is the world’s largest data repository of mass spectrometry-based proteomics data, and is one of the founding members of the global ProteomeXchange (PX) consortium. In this manuscript, we summarize the developments in PRIDE resources and related tools since the previous update manuscript was published in Nucleic Acids Research in 2016. In the last 3 years, public data sharing through PRIDE (as part of PX) has definitely become the norm in the field. In parallel, data re-use of public proteomics data has increased enormously, with multiple applications. We first describe the new architecture of PRIDE Archive, the archival component of PRIDE. PRIDE Archive and the related data submission framework have been further developed to support the increase in submitted data volumes and additional data types. A new scalable and fault tolerant storage backend, Application Programming Interface and web interface have been implemented, as a part of an ongoing process. Additionally, we emphasize the improved support for quantitative proteomics data through the mzTab format. At last, we outline key statistics on the current data contents and volume of downloads, and how PRIDE data are starting to be disseminated to added-value resources including Ensembl, UniProt and Expression Atlas.

... read more

Topics: Information repository (53%)

3,828 Citations