Ebbert MT, Jensen TD, Jansen-West K, Sens JP, Reddy JS, Ridge PG, Kauwe JS, Belzil V, Pregent L, Carrasquillo MM, Keene D, Larson E, Crane P, Asmann YW, Ertekin-Taner N, Younkin SG, Ross OA, Rademakers R, Petrucelli L, Fryer JD. Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight. Genome Biol. 2019 May 20;20(1):97. PubMed.
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University of California, Irvine
As the news article notes, this manuscript does an excellent job of pointing out the caveats of standard short-read sequencing technologies, the basis for the “dark” and “camouflaged” regions, and how these deficiencies impact our effort to map out the genetic basis of human diseases. The authors provide a bioinformatic strategy to rescue mutations in camouflaged regions.
As an example of one such rescued region, they detected a rare 10-nucleotide deletion in the AD GWAS gene CR1 (26 percent dark/camouflaged due to long homologous-repeat regions) which results in a frameshift mutation. In the AD Sequencing Project samples, all five cases of the deletion were detected in AD cases, although there was an insufficient number of cases in the ADSP to reach a conclusion of the relative risk of AD associated with this deletion. The location of this deletion is on exon 10, 18, or 26, which, in the most common form of CR1, corresponds to the first exon of each LHR-B, LHR-C and LHR-D. As the paper states, these LHRs each contain a C3b/C4b binding site.
My comment would be to highlight the novel identification of a potential CR1 risk allele. Given that the 10-nucleotide deletion in CR1 induces a stop codon, which would truncate the protein without the transmembrane domain, the result could be a lower expression of membrane CR1 in the case of heterozygous carriers, and thus quantitative reduction of function. Joe Rogers has provided evidence consistent with CR1-mediated clearance of C3b-tagged amyloid (Johansson et al., 2018; Crane et al., 2017; Brubaker et al., 2017; Rogers et al., 2006). Thus, a CR1 deficiency could contribute to a reduced clearance of at least peripheral/blood amyloid in these individuals, and enhance their susceptibility to accumulate amyloid in the brain, increasing risk for AD.
References:
Johansson JU, Brubaker WD, Javitz H, Bergen AW, Nishita D, Trigunaite A, Crane A, Ceballos J, Mastroeni D, Tenner AJ, Sabbagh M, Rogers J. Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: Polymorphisms, structure, and function of complement receptor 1. Alzheimers Dement. 2018 Nov;14(11):1438-1449. Epub 2018 May 21 PubMed.
Crane A, Brubaker WD, Johansson JU, Trigunaite A, Ceballos J, Bradt B, Glavis-Bloom C, Wallace TL, Tenner AJ, Rogers J. Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: 2. Relationship to Aβ immunotherapy. Alzheimers Dement. 2017 Jul 26; PubMed.
Brubaker WD, Crane A, Johansson JU, Yen K, Garfinkel K, Mastroeni D, Asok P, Bradt B, Sabbagh M, Wallace TL, Glavis-Bloom C, Tenner AJ, Rogers J. Peripheral complement interactions with amyloid β peptide: Erythrocyte clearance mechanisms. Alzheimers Dement. 2017 May 2; PubMed.
Rogers J, Li R, Mastroeni D, Grover A, Leonard B, Ahern G, Cao P, Kolody H, Vedders L, Kolb WP, Sabbagh M. Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol Aging. 2006 Dec;27(12):1733-9. Epub 2005 Nov 14 PubMed.
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