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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
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In addition to multiple alleles at the same locus influencing traits, numerous genes or alleles at different locations may interact and influence phenotypes in a phenomenon called epistasis. For example, rabbit fur can be black or brown depending on whether the animal is homozygous dominant or heterozygous at a TYRP1 locus. However, if the rabbit is also homozygous recessive at a locus on the tyrosinase gene (TYR), it will have an unshaded coat that appears white, regardless of its TYRP1...
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Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
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A Multitrait Locus Regulates Sarbecovirus Pathogenesis.

Alexandra Schäfer1, Sarah R Leist1, Lisa E Gralinski1

  • 1Department of Epidemiology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.

Mbio
|July 21, 2022
PubMed
Summary
This summary is machine-generated.

Host genetic variation impacts infectious disease severity. Researchers identified CCR9 and CXCR6 genes in mice as crucial in regulating outcomes for SARS-CoV, SARS-CoV-2, and other coronaviruses, offering insights into human disease.

Keywords:
SARS-CoV-2collaborative crosshost responsepathogenesissarbecoviruses

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Area of Science:

  • Genetics
  • Immunology
  • Virology

Background:

  • Host genetic variation significantly influences susceptibility and outcomes of infectious diseases, particularly viral infections.
  • Studying human genetic associations with infectious diseases presents challenges, making animal models essential for controlled research.
  • Understanding genetic determinants of severe coronavirus infections is crucial for predicting host susceptibility and mortality.

Purpose of the Study:

  • To investigate the role of host genetic variation in severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes using a mouse model.
  • To identify genetic loci regulating differential disease outcomes in response to SARS-CoV infection.
  • To explore conserved genetic elements between mouse and human studies for SARS-CoV-2.

Main Methods:

  • Utilized a genetic mapping cross between two Collaborative Cross mouse strains to study SARS-CoV disease outcomes.
  • Performed genetic analyses to identify loci associated with differential disease traits.
  • Followed up on identified loci, including a conserved synteny region on mouse chromosome 9, to identify candidate genes.

Main Results:

  • Identified several loci controlling differential disease outcomes in response to SARS-CoV infection.
  • Discovered a significant locus on mouse chromosome 9 with conserved synteny to a human locus associated with SARS-CoV-2 severity.
  • Validated CCR9 and CXCR6 as key genes within this locus, demonstrating their protective role against SARS-CoV, SARS-CoV-2, and a bat sarbecovirus.

Conclusions:

  • Mouse genetic crosses provide a powerful model for identifying and characterizing multitrait loci regulating infectious disease outcomes across species.
  • The identified chromosome 9 locus, containing CCR9 and CXCR6, is a critical regulator of sarbecovirus pathogenesis.
  • CCR9 and CXCR6 play a protective role in severe coronavirus infections, suggesting their potential importance in human disease outcomes.