Abstract
Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1389-1401 |
| Number of pages | 13 |
| Journal | Genome research |
| Volume | 29 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2019 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
The 22q11 low copy repeats are characterized by unprecedented size and structural variability. / Demaerel, Wolfram; Mostovoy, Yulia; Yilmaz, Feyza; Vervoort, Lisanne; Pastor, Steven; Hestand, Matthew S.; Swillen, Ann; Vergaelen, Elfi; Geiger, Elizabeth A.; Coughlin, Curtis R.; Chow, Stephen K.; McDonald-McGinn, Donna; Morrow, Bernice E.; Kwok, Pui Yan; Xiao, Ming; Emanuel, Beverly S.; Shaikh, Tamim H.; Vermeesch, Joris R.
In: Genome research, Vol. 29, No. 9, 01.09.2019, p. 1389-1401.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The 22q11 low copy repeats are characterized by unprecedented size and structural variability
AU - Demaerel, Wolfram
AU - Mostovoy, Yulia
AU - Yilmaz, Feyza
AU - Vervoort, Lisanne
AU - Pastor, Steven
AU - Hestand, Matthew S.
AU - Swillen, Ann
AU - Vergaelen, Elfi
AU - Geiger, Elizabeth A.
AU - Coughlin, Curtis R.
AU - Chow, Stephen K.
AU - McDonald-McGinn, Donna
AU - Morrow, Bernice E.
AU - Kwok, Pui Yan
AU - Xiao, Ming
AU - Emanuel, Beverly S.
AU - Shaikh, Tamim H.
AU - Vermeesch, Joris R.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.
AB - Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.
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U2 - 10.1101/gr.248682.119
DO - 10.1101/gr.248682.119
M3 - Article
VL - 29
SP - 1389
EP - 1401
JO - Genome Research
JF - Genome Research
SN - 1088-9051
IS - 9
ER -