Analysis of allelic expression patterns in clonal somatic cells by single-cell RNA-seq.
Cellular heterogeneity can emerge from the expression of only one parental allele. However, it has remained controversial whether, or to what degree, random monoallelic expression of autosomal genes (aRME) is mitotically inherited (clonal) or stochastic (dynamic) in somatic cells, particularly in vivo. Here we used allele-sensitive single-cell RNA-seq on clonal primary mouse fibroblasts and freshly isolated human CD8+T cells to dissect clonal and dynamic monoallelic expression patterns. Dynamic aRME affected a considerable portion of the cells' transcriptomes, with levels dependent on the cells' transcriptional activity. Notably, clonal aRME was detected, but it was surprisingly scarce (<1% of genes) and mainly affected the most weakly expressed genes. Consequently, the overwhelming majority of aRME occurs transiently within individual cells, and patterns of aRME are thus primarily scattered throughout somatic cell populations rather than, as previously hypothesized, confined to patches of clonally related cells.
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.|Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden.
Björn
B
Reinius
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Jeff E
JE
Mold
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.|Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden.
Daniel
D
Ramsköld
Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden.
Qiaolin
Q
Deng
Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden.
Per
P
Johnsson
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
Jakob
J
Michaëlsson
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Jonas
J
Frisén
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.|Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden.
Rickard
R
Sandberg
D000483:Alleles; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D002999:Clone Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D020641:Polymorphism, Single Nucleotide; D017423:Sequence Analysis, RNA
Cell Stem Cell. 2013 Jul 3;13(1):12-3
23827706
Trends Genet. 2014 Jun;30(6):237-44
24780084
Dev Cell. 2014 Feb 24;28(4):366-80
24576422
Nat Rev Genet. 2012 May 15;13(6):421-8
22585065
Stem Cells. 2012 Sep;30(9):1938-47
22714879
Nat Methods. 2014 Jan;11(1):22-4
24524133
Dev Genes Evol. 1999 Feb;209(2):113-9
10022954
J Immunol. 2013 Mar 1;190(5):2150-8
23338234
Dev Cell. 2014 Feb 24;28(4):351-65
24576421
Genome Res. 2008 May;18(5):821-9
18349386
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15641-6
9861023
Science. 2014 Jan 10;343(6167):193-6
24408435
Nature. 2010 Feb 18;463(7283):913-8
20164922
Bioinformatics. 2013 Jan 1;29(1):15-21
23104886
PLoS One. 2013;8(1):e53822
23349747
Nat Methods. 2013 Sep;10(9):813-4
23892897
Nucleic Acids Res. 2009 Jan;37(1):1-13
19033363
Mol Cell. 2015 Apr 16;58(2):339-52
25866248
Genome Biol. 2012 Feb 20;13(2):R10
22348269
Nat Genet. 1999 Apr;21(4):390-5
10192389
Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):814-9
9023339
Science. 2002 Aug 16;297(5584):1183-6
12183631
Am J Hum Genet. 2015 Jan 8;96(1):70-80
25557783
Nat Methods. 2013 Nov;10(11):1096-8
24056875
Science. 2007 Nov 16;318(5853):1136-40
18006746
Science. 1998 Mar 27;279(5359):2118-21
9516115
Elife. 2013 Dec 31;2:e01256
24381246
Nucleic Acids Res. 2009 Jan;37(Database issue):D1006-12
18978023
PLoS One. 2012;7(2):e31751
22384067
Immunity. 2008 May;28(5):710-22
18468462
Cell Stem Cell. 2013 Jul 3;13(1):23-9
23827708
Nat Rev Genet. 2015 Nov;16(11):653-64
26442639
Science. 1998 Aug 28;281(5381):1352-4
9721100
Nat Methods. 2013 Nov;10(11):1093-5
24056876
Genome Res. 2014 Dec;24(12):2033-40
25079858
Nature. 2012 Feb 12;483(7390):470-3
22327294
Genome Res. 2014 Mar;24(3):496-510
24299736
Nat Genet. 2016 Mar;48(3):231-7
26808112
Genetics. 2015 Jun;200(2):537-49
25858912
Mol Biol Cell. 2002 Jun;13(6):1977-2000
12058064
Nat Protoc. 2009;4(1):44-57
19131956
PLoS Comput Biol. 2009 Dec;5(12):e1000598
20011106
Nucleic Acids Res. 2016 Jan 4;44(D1):D753-6
26503248
Nat Biotechnol. 2007 Feb;25(2):207-15
17287758
Nat Rev Genet. 2005 Jun;6(6):451-64
15883588
Science. 2011 Apr 22;332(6028):472-4
21415320