Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity
- Division of Hematology Oncology, Departments of Medicine and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, United States
- San Diego Biomedical Research Institute, United States
- Department of Orthopedics and Rehabilitation, Oregon Health and Science University, United States
- Shriners Hospitals for Children - Portland, United States
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, United States
- Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, United States
Figures
Figure 1 with 1 supplement
Genome-wide variable replication-timing and expression imbalance.
(a) Single-cell-derived ACP clones (color coded) were isolated, expanded, and processed for Repli-seq and RNA-seq. The maternal and paternal haplotypes were used to analyze allele-specific replication timing and expression. (b) The top panel illustrates the expected replication timing profile in multiple clones across an autosomal region. The regions that display VERT are highlighted by shading. The bottom panel illustrates the expected expression variability in different clones from the same individual. (c) We define VERT regions in Repli-seq data across each allele for each 250-kb genomic window. Windows with an SD value ≥2.5 standard deviations above the genome-wide median were classified as outliers (top panels). We define AEI as an allelic bias that is ≥80% allelic imbalance (AEI ≥0.80 or ≤0.20). The bottom panel shows both autosomal and X-linked expression data. (d) Illustration of an Inactivation/Stability Center (I/SC) showing the clonal and allele-restricted variability in replication timing and expression of both protein-coding and noncoding genes. (e) The standard deviation (Std. Dev.) in 250-kb windows (circles) across human chromosome 1. Outlier windows from all four sets of clones (ACP6, ACP7, EB3-2, and GM12878) are highlighted in different colors as shown. The top panel illustrates the G-banding (blue shading) pattern for human chromosome 1, with 23 VERT regions highlighted in red. The location of an imprinted region with asynchronous replication, containing the maternally expressed TP73 gene (https://geneimprint.com/), is marked with an +. The arrow marks the VERT region shown in panels f–h. (f–h) I/SC located between 239 and 242 Mb of chromosome 1 (see panel e). (f) VERT (shaded region) and AEI of genes (rectangles) detected in the ACP6 clones; each clone was color coded as shown. For replication, the solid lines represent the paternal (Hap1) allele, and the dotted line represents the maternal (Hap2) allele. (g) VERT (shaded region) and AEI of genes (rectangles) detected in the ACP7 clones; each clone was color coded as shown. (h) UCSC Genome Browser view of the genomic region in panels f and g. The shaded area highlights the VERT region. The asterisks mark the genes highlighted in panels f and g. (i) Venn diagram illustrating the number of VERT regions that overlap between the different clonal populations. (j) Gene Ontology (GO) enrichment analysis of the genes located within the VERT regions; the most significant hits for each set of clones, organized by cell type, are shown. GO analysis of the mouse genes located within the pre-B cell clone VERT regions is also shown.
-
Figure 1—source data 1
This file lists the location of the VERT regions detected in the human genome.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig1-data1-v1.xlsx
-
Figure 1—source data 2
This file shows the number of haplotype phased sequence reads detected by RNAseq within coding genes.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig1-data2-v1.xlsx
-
Figure 1—source data 3
This file shows the number of haplotype phased sequence reads detected by RNAseq within non-coding genes.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig1-data3-v1.xlsx
-
Figure 1—source data 4
This file contains the number of transcripts derived from the early or late replicating alleles for Figures 1, 2 and 6 and Figure 1—figure supplement 1.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig1-data4-v1.xlsx
-
Figure 1—source data 5
This file contains the list of human protein coding genes located within VERT regions.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig1-data5-v1.xlsx
-
Figure 1—source data 6
This file contains the Gene Ontology analysis for the genes located in VERT regions.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig1-data6-v1.xlsx
Figure 1—figure supplement 1
Imprinted regions display asynchronous replication.
(a, d) VERT regions on human chromosomes 14 and 20. The standard deviation in 250-kb windows (circles) is shown. Outlier windows from all four sets of clones (ACP6, ACP7, EB3-2, and GM12878) are highlighted in different colors as shown. The regions highlighted by the red boxes mark known imprinted loci. (b, e) For replication timing, solid lines represent the paternal allele (Hap1), and the dotted line represents the maternal allele (Hap2). The regions with asynchrony are shaded, and the gene expression is shown for each clone in a different color. (c) UCSC Genome Browser view of the asynchronous region in panel a. (b, c) The single asterisk marks the paternally expressed DLK gene, and the double asterisks mark the maternally expressed MEG8 gene. (f) UCSC Genome Browser view of the VERT region in panel d. (e, f) The # marks the paternally expressed L3MBTL1 gene.
Figure 2
Examples of Inactivation/Stability Centers (I/SCs).
(a, d, g) VERT regions on human chromosomes 18, 6, and 9, respectively. The top panels illustrate the G-banding (blue shading) pattern for each human chromosome, with VERT regions highlighted in red. The standard deviation (Std. Dev.) in 250-kb windows (circles) across each human chromosome is shown. Outlier windows from all four sets of clones (ACP6, ACP7, EB3-2, and GM12878) are highlighted in different colors as shown. The arrows and red boxes mark the VERT regions shown in panels b, e, h. (b, e, h) I/SCs highlighted in panels a, d, and g. For replication, the solid lines represent the paternal (Hap1) allele, and the dotted lines represent the maternal (Hap2) allele. The regions with VERT are shaded, and the AEI is shown for each clone in different colors. The location of an imprinted region with asynchronous replication, containing the paternally expressed LIN28B gene (https://geneimprint.com/), is marked with an + in panel d. (c, f, i) UCSC Genome Browser views of the genomic regions in panels b, e, and h. The shaded areas highlight the VERT regions. Genes with AEI are marked with +, *, or #. (b, c) The + marks MOCOS, which shows AEI in ACP cells (Figure 1—source data 2), and ++ marks FHOD3, which shows AEI in LCLs (Heskett et al., 2022). (e, f) The * marks transcripts from DNAH8, ** marks transcripts from KCNK5, and *** marks non-coding transcripts from ENSG00000293066 (also named: TL:6–39.9_1 Heskett et al., 2022). All three of these genes show AEI in LCL clones (Heskett et al., 2022). (h, i) The # marks transcripts from DAPK1, ## marks transcripts from SPIN1. Both genes show AEI in LCL clones (Heskett et al., 2022).
-
Figure 2—source data 1
This file contains the list of VERT regions that contain genes with AEI.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig2-data1-v1.xlsx
Figure 3
Human gene clusters with AEI map to VERT regions.
(a, c) VERT regions on human chromosomes 19 and 6, respectively. The top panels illustrate the G-banding (blue shading) pattern for each human chromosome, with VERT regions highlighted in red. The standard deviation (Std. Dev.) in 250-kb windows (circles) across each human chromosome is shown. Outlier windows from all four sets of clones (ACP6, ACP7, EB3-2, and GM12878) are highlighted in different colors as shown. The red boxes and arrows identify the Inactivation/Stability Centers (I/SCs) in panels b and d. The location of an imprinted region with asynchronous replication, containing the paternally expressed LIN28B gene (https://geneimprint.com/), is marked with an + in panel c. (b) UCSC genome browser view illustrating the genomic location highlighted in panel a. The shaded area highlights the VERT region. The red underlines mark 11 olfactory receptor genes, and the green underlines mark 6 cytochrome P450 family (CYP4F) genes. (d) UCSC Genome Browser view illustrating the genomic location highlighted in panel c. The shaded area highlights the VERT region. The red underlines mark 16 HLA genes, and the green underlines mark 6 Lymphocyte antigen 6 family (LY6G) genes.
Figure 4 with 1 supplement
Mouse gene clusters with AEI map to VERT regions.
(a, d) VERT regions on mouse chromosomes 2 and 18, respectively. The standard deviation (Std. Dev.) in 50-kb windows (circles) across each mouse chromosome are shown. Outlier windows from pre-B cell clones are highlighted in orange. The red boxes and arrows identify the VERT regions in panels b (i) and c (ii). (b, c) UCSC genome browser views illustrating the genomic locations represented by i and ii in panel a. (b) Genome Browser view of the VERT region showing the location of 29 olfactory receptor genes (Or genes). The shaded area represents the VERT region. (c) Genome Browser view of the VERT region in ii above, showing the location of 242 olfactory receptor genes (Or genes). The shaded area represents the VERT region. (e) Genome Browser view of the VERT region in panel d, showing the location of clustered Protocadherin genes (15 Pcdha, 23 Pcdhb, and 22 Pcdhg genes). The shaded area represents the VERT region.
-
Figure 4—source data 1
This file contains the list of mouse genes located within VERT regions in the mouse genome.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig4-data1-v1.xlsx
Figure 4—figure supplement 1
VERT detected at the mouse T cell receptor alpha locus.
UCSC Genome Browser view of the mouse VERT region (shaded) detected at the T cell receptor alpha (Tra) locus on mouse chromosome 14. The location of 37 Or genes, marked by red underlines, and the vomeronasal receptor gene Vmn2r88, marked by a green underline.
Figure 5 with 1 supplement
Human and mouse syntenic regions display VERT.
The short arm of human chromosome 5, with 11 VERT regions (panel a) and the centromeric region of mouse chromosome 15, with 4 VERT regions (panel b) are shown. (a) Two human VERT regions are highlighted, hi and hii, and are syntenic with locations on mouse chromosome 15, mi and mii, that also show VERT (panel b). Note that the gene order in both syntenic regions are inverted with respect to the telomeres when comparing the human and mouse loci. (c) Illustration of the I/SC on human chromosome 5 between 7.75 and 10.5 mb (hi). The shaded area marks the VERT region, and AEI of the coding gene SEMA5A in different clones is highlighted. For replication, the paternal (Hap1) and maternal (Hap2) alleles are indicated. (d) UCSC Genome Browser view of the human VERT region (shaded) in hi, showing the location of SEMA5A and a taste receptor gene (TAS2R1). (e) UCSC Genome Browser view of the mouse VERT region (shaded) in mi, showing the location of Sema5a and a taste receptor gene (Tas2r119). (f) UCSC Genome Browser view of the human VERT region (shaded) in hii above, highlighting the location of the AEI gene RETREG1 (Gimelbrant et al., 2007). (g) UCSC Genome Browser view of the mouse VERT region (shaded) in mii, showing the synteny between human and mouse for the protein-coding genes in panel f, including Retreg1. (h) VERT regions on human chromosome 16. The standard deviation (Std. Dev.) in 250 kb windows (circles) across human chromosome 16 is shown. Outlier windows are highlighted in different colors as shown. The red box and arrow mark the genomic location in panel i. (i) UCSC Genome Browser view illustrating the genomic location represented in panel h, showing the location of GRIN2A (red box). (j) VERT regions on mouse chromosome 16. The standard deviation in 50-kb windows (circles) is shown. Outlier windows from pre-B cell clones are highlighted in orange. (k) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) represented in panel j above, with the location of Grin2a highlighted with a red box.
-
Figure 5—source data 1
This file contains the list of mouse genes within VERT regions that have corresponding human genetic diseases.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig5-data1-v1.xlsx
Figure 5—figure supplement 1
Mouse syntenic regions display VERT.
(a, c, e) VERT regions on mouse chromosomes 16, 2, and 18. The standard deviation in 50-kb windows (circles) is shown. Outlier windows from pre-B cell clones are highlighted in orange. The VERT regions highlighted by red boxes are expanded in panels b, d, and f. (b) UCSC Genome Browser view of the VERT region in a above, highlighting the location of the mouse App gene (red box). The shaded area represents the VERT region. (d) UCSC Genome Browser view of the VERT region in panel c, highlighting the location of the mouse Mocos and Fhod3 genes (red boxes). The shaded area represents the VERT region. (f) UCSC Genome Browser view of the VERT region in panel c, highlighting the location of five mouse Scn genes (red boxes). The shaded area represents the VERT region.
Figure 6
Epilepsy genes map to Inactivation/Stability Centers (I/SCs).
(a, d, g) VERT regions on human chromosomes 2, 5, and 8, respectively. The top panels illustrate the G-banding (blue shading) pattern for each human chromosome, with VERT regions highlighted in red. The standard deviation (Std. Dev.) in 250-kb windows (circles) across each human chromosome is shown. Outlier windows from all four sets of clones (ACP6, ACP7, EB3-2, and GM12878) are highlighted in different colors as shown. The location of an imprinted region with asynchronous replication, containing the paternally expressed DLGAP2 gene (https://geneimprint.com/), is marked with an + in panel g. The arrows and red boxes mark the VERT regions shown in panels b, c, e, f, and h–k. (b, e, h, j) Illustrations of I/SCs on chromosomes 2, 5, and 8, respectively. The shaded areas mark the VERT regions. Each clone was color coded to illustrate the VERT and AEI in different clones. The paternal (Hap1) and maternal (Hap2) alleles are indicated for replication and expression. (c) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) represented in panels a and b, with the location of five sodium channel genes (SCN3A, SCN2A, SCN1A, SCN9A, and SCN7A) highlighted with red underlines. (e) Illustration of an I/SC on chromosome 5. The shaded area marks the VERT region. AEI of GABRA1 is shown. (f) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) represented in panels d and e above, with the location of four GABA receptor genes (GABRB2, GABRBA6, GABRA1, and GABRG2) highlighted with red underlines. (h) Illustration of an I/SC (A and red box) on chromosome 8. Each ACP6 clone was color coded to illustrate the VERT and AEI in different clones. The paternal (Hap1) and maternal (Hap2) alleles are indicated for replication and expression. The shaded area marks the VERT region. The location and expression of OXR1 is indicated. (i) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) represented in panels g (A) and h, with the location of the OXR1 gene highlighted with a red underline. We note that ANGPT1 (marked with *), located within this I/SC displays AEI (see Figure 1—source data 2). (j) Illustration of an I/SC (B and red box) on chromosome 8. AEI of SAMD12 is indicated. (k) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) represented in panels g (B) and j, with the location of the SAMD12 highlighted with a red underline.
-
Figure 6—source data 1
This file lists the human disease genes located within VERT regions.
- https://cdn.elifesciences.org/articles/109938/elife-109938-fig6-data1-v1.xlsx
Figure 7
Parkinson disease genes map to Inactivation/Stability Centers (I/SCs).
(a, c, e, g) VERT regions on human chromosomes 4, 12, 1, and 6, respectively. The top panels illustrate the G-banding (blue shading) pattern for each human chromosome, with VERT regions highlighted in red. The standard deviation (Std. Dev.) in 250-kb windows (circles) across each human chromosome is shown. Outlier windows from all four sets of clones (ACP6, ACP7, EB3-2, and GM12878) are highlighted in different colors as shown. The location of an imprinted region with asynchronous replication, containing the paternally expressed LIN28B gene (https://geneimprint.com/), is marked with an + in panel g. The location of an imprinted region with asynchronous replication, containing the maternally expressed TP73 gene (https://geneimprint.com/), is marked with an + in panel e. The arrows and red boxes mark the VERT regions shown in panels b, d, f, and h, respectively. (b) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) represented in panel a, with the location of the SNCA gene highlighted with a red underline. (d) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) highlighted in panel c, with the location of the LRRK2 gene highlighted with a red underline. (f) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) represented in panel e, with the location of the DNAJC6 gene highlighted with a red underline; also highlighted with a green underline is the JAK1 gene. (h) UCSC Genome Browser view illustrating the genomic location of the VERT region (shaded area) represented in panel g, with the location of the PRKN gene highlighted with a red underline.
Tables
Table 1
VERT regions at gene clusters in the human and mouse genomes.
| Human VERT region | Gene cluster | |||||
|---|---|---|---|---|---|---|
| Chr | Start | Stop | Genes | # of genes | Start | Stop |
| 1 | 13,250,000 | 15,000,000 | PRAMEF | 23 | 12,768,939 | 13,422,488 |
| 2 | 101,633,538 | 102,383,540 | IL1R | 5 | 101,987,899 | 102,401,443 |
| 2 | 165,250,000 | 166,000,000 | SCN | 5 | 165,081,204 | 166,499,088 |
| 2 | 176,250,000 | 176,500,000 | HOXD | 9 | 176,091,062 | 176,191,493 |
| 4 | 46,750,000 | 47,500,000 | GABR | 4 | 46,035,583 | 47,431,569 |
| 4 | 68,384,282 | 68,634,282 | UGT | 9 | 68,525,283 | 69,660,413 |
| 5 | 651,700 | 750,000 | SLC | 5 | 468,888 | 1,448,927 |
| 5 | 148,000,000 | 148,250,000 | SPINK | 7 | 147,822,992 | 148,343,066 |
| 5 | 162,250,000 | 162,750,000 | GABR | 4 | 161,282,809 | 162,159,566 |
| 6 | 31,250,000 | 32,750,000 | HLA | 15 | 30,489,509 | 33,093,613 |
| LY6 | 6 | 31,669,259 | 31,722,476 | |||
| 8 | 11,250,000 | 12,392,491 | DEFB | 6 | 11,970,747 | 12,320,078 |
| 8 | 80,587,765 | 83,000,000 | FABP | 4 | 81,277,942 | 81,536,065 |
| 8 | 142,500,000 | 142,750,000 | LY6 | 8 | 142,695,707 | 143,162,219 |
| 11 | 104,750,000 | 105,000,000 | CASP | 5 | 104,883,181 | 105,141,441 |
| 15 | 23,357,400 | 23,500,000 | GOLGA | 5 | 22,451,995 | 23,451,545 |
| 15 | 28,750,000 | 29,000,000 | GOLGA | 6 | 28,344,604 | 28,855,059 |
| 17 | 9,750,000 | 10,500,000 | MYH | 6 | 10,297,552 | 10,658,865 |
| 19 | 15,000,000 | 15,250,000 | OR | 11 | 14,792,476 | 15,952,060 |
| CYP | 6 | 15,507,105 | 15,936,041 | |||
| 19 | 20,750,000 | 21,000,000 | ZNF | 37 | 19,667,773 | 24,119,420 |
| 19 | 36,313,700 | 36,500,000 | ZNF | 29 | 36,171,632 | 37,791,237 |
| 19 | 43,000,000 | 43,250,000 | PSG | 10 | 42,713,521 | 43,272,861 |
| 20 | 24,250,000 | 24,750,000 | CST | 11 | 23,429,902 | 24,957,423 |
| 21 | 30,627,681 | 30,877,681 | KRTAP | 33 | 30,276,201 | 31,041,124 |
| Mouse VERT region | Gene cluster | |||||
| Chr | Start | Stop | Genes | # of genes | Start | Stop |
| 2 | 36,322,857 | 36,622,857 | Or | 28 | 36,225,624 | 37,193,679 |
| 2 | 64,622,866 | 66,522,868 | Scn | 5 | 65,287,042 | 66,637,709 |
| 2 | 88,950,000 | 89,950,000 | Or | 239 | 85,160,859 | 90,147,389 |
| 4 | 59,850,000 | 59,950,000 | Mup | 22 | 59,950,000 | 61,824,646 |
| 5 | 91,150,000 | 91,350,000 | Cxcl | 5 | 91,186,938 | 91,335,955 |
| 5 | 95,950,000 | 96,250,000 | Pramel | 23 | 93,891,822 | 96,243,866 |
| 6 | 40,650,000 | 41,150,000 | Tas2r | 8 | 40,386,430 | 43,196,843 |
| Or | 24 | 40,386,430 | 43,196,843 | |||
| 6 | 66,650,000 | 66,850,000 | Vmn1 | 8 | 66,498,911 | 66,758,688 |
| 7 | 113,809,945 | 113,909,945 | Or | 24 | 113,790,926 | 114,306,041 |
| 11 | 73,450,000 | 74,050,000 | Or | 31 | 73,160,403 | 74,180,092 |
| 18 | 37,350,000 | 37,750,000 | Pcdh | 23 | 37,298,052 | 37,684,088 |
Table 2
VERT regions showing synteny between human and mouse genomes.
| Mouse VERT | Human syntenic region | Human VERT | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Chr | Start | Stop | Synteny (%) | Chr | Start | Stop | Chr | Start | Stop |
| 1 | 73,042,585 | 73,542,585 | 54.0 | 2 | 216,836,864 | 217,400,721 | 2 | 217,000,000 | 217,250,000 |
| 1 | 88,681,147 | 89,081,147 | 33.0 | 2 | 234,565,154 | 235,053,857 | 2 | 234,000,000 | 235,000,000 |
| 1 | 189558318 | 189,758,318 | 49.8 | 1 | 214,144,079 | 214,410,956 | 1 | 214,326,657 | 216,000,000 |
| 2 | 64,842,287 | 66,742,287 | 46.5 | 2 | 164,610,983 | 166,685,353 | 2 | 165,250,000 | 166,000,000 |
| 3 | 18,204,164 | 18,404,164 | 33.7 | 8 | 64,684,742 | 64,876,026 | 8 | 64,337,443 | 65,087,765 |
| 3 | 57,253,499 | 58,553,499 | 32.6 | 3 | 149,407,811 | 150,704,641 | 3 | 149,282,213 | 150,032,213 |
| 3 | 78,253,385 | 78,653,385 | 26.1 | 4 | 159,655,594 | 159,952,325 | 4 | 159,328,848 | 159,828,848 |
| 3 | 82,453,385 | 82,853,385 | 32.6 | 4 | 154,688,934 | 155,210,940 | 4 | 154,500,000 | 154,750,000 |
| 4 | 105034592 | 105,234,592 | 62.8 | 1 | 56,331,724 | 56,556,339 | 1 | 55,500,000 | 56,750,000 |
| 4 | 142286667 | 142,686,667 | 40.6 | 1 | 14,022,915 | 14,523,879 | 1 | 13,250,000 | 15,000,000 |
| 8 | 10,500,000 | 11,200,000 | 43.2 | 13 | 108,978,718 | 110,065,357 | 13 | 109,250,000 | 109,500,000 |
| 8 | 24,029,544 | 24,929,544 | 37.3 | 8 | 40,152,844 | 41,090,451 | 8 | 40,250,000 | 40,750,000 |
| 8 | 39,817,687 | 40,717,687 | 28.6 | 8 | 15,936,545 | 16,964,053 | 8 | 15,750,000 | 17,000,000 |
| 9 | 116969950 | 117,469,950 | 42.3 | 3 | 28,837,647 | 29,402,683 | 3 | 29,000,000 | 29,500,000 |
| 11 | 46,927,325 | 48,127,325 | 35.2 | 5 | 155,465,678 | 156,698,430 | 5 | 155,500,000 | 156,250,000 |
| 12 | 33,715,134 | 33,815,134 | 36.1 | 7 | 19,330,767 | 19,416,599 | 7 | 19,250,000 | 19,500,000 |
| 12 | 105278049 | 105,578,049 | 41.6 | 14 | 95,853,630 | 96,269,387 | 14 | 96,000,000 | 96,250,000 |
| 13 | 11,095,964 | 11,672,619 | 29.9 | 1 | 237,711,340 | 238,470,922 | 1 | 237,604,200 | 238,750,000 |
| 15 | 25,120,331 | 25,920,331 | 42.9 | 5 | 16,534,412 | 17,724,462 | 5 | 16,250,000 | 17,000,000 |
| 15 | 32,220,391 | 32,420,391 | 60.7 | 5 | 9,377,059 | 9,575,503 | 5 | 8,749,888 | 9,499,888 |
| 16 | 9,067,771 | 9,667,771 | 41.6 | 16 | 9,476,924 | 10,028,307 | 16 | 9,750,000 | 10,000,000 |
Table 3
Neurodevelopmental genes within VERT regions.
| VERT gene | Epilepsy disease genes (inheritance: autosomal recessive—AR; autosomal dominant—AD; loss of function—LoF; gain of function—GoF) | Reference |
|---|---|---|
| ALG14 | Myasthenic syndrome (AR); intellectual developmental disorder with epilepsy (AR); myopathy, epilepsy, and progressive cerebral atrophy (AR) | McKusick, 2025 |
| CACNA2D1 | Developmental and epileptic encephalopathy (AR) | McKusick, 2025 |
| GABRB1 | Developmental and epileptic encephalopathy (AD, LoF, GoF) | Hernandez et al., 2023 |
| GRIN2A | Epilepsy (AD, LoF) | Reutlinger et al., 2010 |
| NTRK2 | Developmental and epileptic encephalopathy (AD); obesity (AD) | Hamdan et al., 2017 |
| OXR1 | Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay (AR) | McKusick, 2025 |
| RAPGEF2 | Epilepsy, familial adult myoclonic (AD, TTTCA repeat expansion) | Depienne et al., 2023 |
| RNF13 | Developmental and epileptic encephalopathy (AD, GoF) | Edvardson et al., 2019 |
| SAMD12 | Epilepsy (AD, TTTCA repeat expansion) | Depienne et al., 2023 |
| SCN1A | Developmental and epileptic encephalopathy (AD, LoF); Dravet syndrome (AD, LoF); generalized epilepsy with febrile seizures (AD, LoF) | Ding et al., 2021 |
| SCN2A | Developmental and epileptic encephalopathy (AD, LoF, GoF) | Wolff et al., 2017 |
| VERT gene | Intellectual developmental genes (inheritance: autosomal recessive—AR; autosomal dominant—AD; loss of function—LoF; gain of function—GoF) | Reference |
| ALG14 | Intellectual developmental disorder with epilepsy (AR); myasthenic syndrome (AR); myopathy, epilepsy, and progressive cerebral atrophy (AR) | McKusick, 2025 |
| CEP104 | Intellectual developmental disorder (AR); Joubert syndrome (AR) | McKusick, 2025 |
| CNOT2 | Intellectual developmental disorder (AD, LoF) | Uehara et al., 2019 |
| DPP6 | Intellectual developmental disorder (AD, LoF) | Liao et al., 2013 |
| ELP2 | Intellectual developmental disorder (AR) | McKusick, 2025 |
| FMN2 | Intellectual developmental disorder (AR) | McKusick, 2025 |
| GRIA1 | Intellectual developmental disorder (AD, GoF; AR, LoF) | Ismail et al., 2022 |
| IMPA1 | Intellectual developmental disorder (AR) | McKusick, 2025 |
| IQSEC1 | Intellectual developmental disorder (AR) | McKusick, 2025 |
| MYT1L | Intellectual developmental disorder (AD, LoF) | Blanchet et al., 2017 |
| PDZD8 | Intellectual developmental disorder (AR) | McKusick, 2025 |
| RSRC1 | Intellectual developmental disorder (AR) | McKusick, 2025 |
| TAF4 | Intellectual developmental disorder (AD, LoF) | Bertoli-Avella et al., 2021 |
| TNIK | Intellectual developmental disorder (AR) | McKusick, 2025 |
| TUSC3 | Intellectual developmental disorder (AR) | McKusick, 2025 |
| ZBTB18 | Intellectual developmental disorder (AD, LoF) | Cohen et al., 2017 |
| VERT gene | Neurodevelopment disease genes (inheritance: autosomal recessive—AR; autosomal dominant—AD; loss of function—LoF; gain of function—GoF) | Reference |
| ATP8A2 | Cerebellar ataxia (AR) | McKusick, 2025 |
| CSNK2B | Poirier–Bienvenu neurodevelopmental syndrome (AD, LoF) | Sakaguchi et al., 2017 |
| DPH5 | Neurodevelopmental disorder (AR) | McKusick, 2025 |
| KCNA1 | Episodic ataxia/myokymia syndrome (AD, LoF, GoF) | Paulhus et al., 2020; Müller et al., 2023 |
| LMBRD2 | Developmental delay with variable neurologic and brain abnormalities (AD) | McKusick, 2025 |
| NBEA | Neurodevelopmental disorder (AD, LoF) | Boulin et al., 2021 |
| RETREG1 | Neuropathy (AR) | McKusick, 2025 |
| ROBO1 | Nystagmus (AR); neurooculorenal syndrome (AR); pituitary hormone deficiency (AD) | McKusick, 2025 |
| TIAM1 | Neurodevelopmental disorder (AR) | McKusick, 2025 |
| TRPM3 | Neurodevelopmental disorder (AD, GoF) | Zhao et al., 2020 |
| VARS1 | Neurodevelopmental disorder with microcephaly (AR) | McKusick, 2025 |
| ZSWIM6 | Acromelic frontonasal dysostosis (AD); neurodevelopmental disorder (AD, GoF) | Palmer et al., 2017; Jaillard et al., 2011 |
| VERT gene | Parkinson disease gene (inheritance: autosomal recessive—AR; autosomal dominant—AD; loss of function—LoF; gain of function—GoF) | Reference |
| DNAJC6 | Parkinson disease 19 (AR) | McKusick, 2025 |
| LRRK2 | Parkinson disease (AD, GoF) | Ohta et al., 2013; Taymans et al., 2023 |
| PRKN | Parkinson disease (AR) | McKusick, 2025 |
| SLC18A2 | Parkinsonism-dystonia (AR) | McKusick, 2025 |
| SNCA | Parkinson disease 1 and 4 (AD, LoF/GoF) | Kobayashi et al., 2003; Konno et al., 2016; Blauwendraat et al., 2021 |
Additional files
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity
eLife 15:RP109938.
https://doi.org/10.7554/eLife.109938.4
