Limits...
Chromosome substitution strain assessment of a Huntington's disease modifier locus.

Ramos EM, Kovalenko M, Guide JR, St Claire J, Gillis T, Mysore JS, Sequeiros J, Wheeler VC, Alonso I, MacDonald ME - Mamm. Genome (2015)

Bottom Line: Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes.These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains.This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA, esilvaramos@mgh.harvard.edu.

ABSTRACT
Huntington's disease (HD) is a dominant neurodegenerative disorder that is due to expansion of an unstable HTT CAG repeat for which genome-wide genetic scans are now revealing chromosome regions that contain disease-modifying genes. We have explored a novel human-mouse cross-species functional prioritisation approach, by evaluating the HD modifier 6q23-24 linkage interval. This unbiased strategy employs C57BL/6J (B6J) Hdh(Q111) knock-in mice, replicates of the HD mutation, and the C57BL/6J-chr10(A/J)/NaJ chromosome substitution strain (CSS10), in which only chromosome 10 (chr10), in synteny with the human 6q23-24 region, is derived from the A/J (AJ) strain. Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes. Testing of F1 progeny confirmed that a single AJ chromosome had a significant effect on the rate of body weight gain and in Hdh(Q111) mice the AJ chromosome was associated subtle alterations in somatic CAG instability in the liver and the formation of intra-nuclear inclusions, as well as DARPP-32 levels, in the striatum. These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains. This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

Show MeSH

Related in: MedlinePlus

Genetic architecture of the ~131 Mbp mouse chr10. a Representative homology scheme of mouse chr10 compared with human. b Location of the reported genetic variants between B6J and AJ strains at mouse chr10. Coding non-synonymous variants are represented in red, coding synonymous in dark blue, locus-region in orange, mRNA-UTR in purple, splice-site in light blue and intronic in grey (Color figure online)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4372682&req=5

Fig2: Genetic architecture of the ~131 Mbp mouse chr10. a Representative homology scheme of mouse chr10 compared with human. b Location of the reported genetic variants between B6J and AJ strains at mouse chr10. Coding non-synonymous variants are represented in red, coding synonymous in dark blue, locus-region in orange, mRNA-UTR in purple, splice-site in light blue and intronic in grey (Color figure online)

Mentions: A genome wide HD modifier linkage scan has provided strong evidence for a QTL, between markers D6S1009 and D6S2436, at the human 6q23–24 interval, that modulates age at HD neurological onset (Li et al. 2003, 2006). This region (~16 Mbp) includes at least 80 different human genes that corresponded to 72 homologue genes in the mouse, as annotated in the Ensembl Genome Browser (Flicek et al. 2013). The human 6q23–24 interval is in synteny with part of mouse chr10 (Fig. 2a), comprising 71 of the homologue genes. According to the Mouse Genome Informatics database (Eppig et al. 2012), B6J and AJ mice have about 16,000 allelic differences at chr10 (~131 Mbp): 106 non-synonymous, 205 synonymous, ~14,600 intronic, 576 locus-region (in an untranscribed region flanking a gene: 2 Kb 5′ or 0.5 Kb 3′), 316 mRNA-UTR (in the transcript but not in the coding region interval) and 3 splice-site (in the first or two last bases of an intron) variants (Fig. 2b). From these variants, 19 coding non-synonymous SNPs, most likely to have functional impact, are located in 12 homologues of human genes located at 6q23–24: Mthfd1 l, 1700052N19Rik, Katna1, Sash1, Samd5, Epm2a, Utrn, Stx11, Hivep2, Nhsl1, Tnfaip3 and Ifngr1.Fig. 2


Chromosome substitution strain assessment of a Huntington's disease modifier locus.

Ramos EM, Kovalenko M, Guide JR, St Claire J, Gillis T, Mysore JS, Sequeiros J, Wheeler VC, Alonso I, MacDonald ME - Mamm. Genome (2015)

Genetic architecture of the ~131 Mbp mouse chr10. a Representative homology scheme of mouse chr10 compared with human. b Location of the reported genetic variants between B6J and AJ strains at mouse chr10. Coding non-synonymous variants are represented in red, coding synonymous in dark blue, locus-region in orange, mRNA-UTR in purple, splice-site in light blue and intronic in grey (Color figure online)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4372682&req=5

Fig2: Genetic architecture of the ~131 Mbp mouse chr10. a Representative homology scheme of mouse chr10 compared with human. b Location of the reported genetic variants between B6J and AJ strains at mouse chr10. Coding non-synonymous variants are represented in red, coding synonymous in dark blue, locus-region in orange, mRNA-UTR in purple, splice-site in light blue and intronic in grey (Color figure online)
Mentions: A genome wide HD modifier linkage scan has provided strong evidence for a QTL, between markers D6S1009 and D6S2436, at the human 6q23–24 interval, that modulates age at HD neurological onset (Li et al. 2003, 2006). This region (~16 Mbp) includes at least 80 different human genes that corresponded to 72 homologue genes in the mouse, as annotated in the Ensembl Genome Browser (Flicek et al. 2013). The human 6q23–24 interval is in synteny with part of mouse chr10 (Fig. 2a), comprising 71 of the homologue genes. According to the Mouse Genome Informatics database (Eppig et al. 2012), B6J and AJ mice have about 16,000 allelic differences at chr10 (~131 Mbp): 106 non-synonymous, 205 synonymous, ~14,600 intronic, 576 locus-region (in an untranscribed region flanking a gene: 2 Kb 5′ or 0.5 Kb 3′), 316 mRNA-UTR (in the transcript but not in the coding region interval) and 3 splice-site (in the first or two last bases of an intron) variants (Fig. 2b). From these variants, 19 coding non-synonymous SNPs, most likely to have functional impact, are located in 12 homologues of human genes located at 6q23–24: Mthfd1 l, 1700052N19Rik, Katna1, Sash1, Samd5, Epm2a, Utrn, Stx11, Hivep2, Nhsl1, Tnfaip3 and Ifngr1.Fig. 2

Bottom Line: Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes.These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains.This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA, esilvaramos@mgh.harvard.edu.

ABSTRACT
Huntington's disease (HD) is a dominant neurodegenerative disorder that is due to expansion of an unstable HTT CAG repeat for which genome-wide genetic scans are now revealing chromosome regions that contain disease-modifying genes. We have explored a novel human-mouse cross-species functional prioritisation approach, by evaluating the HD modifier 6q23-24 linkage interval. This unbiased strategy employs C57BL/6J (B6J) Hdh(Q111) knock-in mice, replicates of the HD mutation, and the C57BL/6J-chr10(A/J)/NaJ chromosome substitution strain (CSS10), in which only chromosome 10 (chr10), in synteny with the human 6q23-24 region, is derived from the A/J (AJ) strain. Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes. Testing of F1 progeny confirmed that a single AJ chromosome had a significant effect on the rate of body weight gain and in Hdh(Q111) mice the AJ chromosome was associated subtle alterations in somatic CAG instability in the liver and the formation of intra-nuclear inclusions, as well as DARPP-32 levels, in the striatum. These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains. This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

Show MeSH
Related in: MedlinePlus