Janet M Young

• PhD
• Researcher at Fred Hutch Cancer Center

Human Immunodeficiency Virus (HIV) relies on host molecular machinery for replication. Systematic attempts to genetically or biochemically define these host factors have yielded hundreds of candidates, but few have been functionally validated in primary cells. Here, we target 426 genes previously implicated in the HIV lifecycle through protein inte...

Histones and their post-translational modifications facilitate diverse chromatin functions in eukaryotes. Core histones (H2A, H2B, H3, and H4) package genomes after DNA replication. In contrast, variant histones promote specialized chromatin functions, including DNA repair, genome stability, and epigenetic inheritance. Previous studies have identif...

Most actin-related proteins (Arps) are highly conserved and carry out well-defined cellular functions in eukaryotes. However, many lineages like Drosophila and mammals encode divergent non-canonical Arps whose roles remain unknown. To elucidate the function of non-canonical Arps, we focus on Arp53D, which is highly expressed in testes and retained...

RNA helicases and E3 ubiquitin ligases mediate many critical functions in cells, but their actions have largely been studied in distinct biological contexts. Here, we uncover evolutionarily conserved rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immun...

Contrary to dogma, evolutionarily young and dynamic genes can encode essential functions. We find that evolutionarily dynamic ZAD-ZNF genes, which encode the most abundant class of insect transcription factors, are more likely to encode essential functions in Drosophila melanogaster than ancient, conserved ZAD-ZNF genes. We focus on the Nicknack ZA...

Antagonistic coevolution with selfish genetic elements (SGEs) can drive evolution of host resistance. Here, we investigated host suppression of 2-micron (2m) plasmids, multicopy nuclear parasites that have co-evolved with budding yeasts. We developed SCAMPR (Single-Cell Assay for Measuring Plasmid Retention) to measure copy number heterogeneity and...

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by l...

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, t...

Although most unicellular organisms reproduce asexually, most multicellular eukaryotes are obligately sexual. This implies that there are strong barriers that prevent the origin or maintenance of asexuality arising from an obligately sexual ancestor. By studying rare asexual animal species we can gain a better understanding of the circumstances tha...

Although most unicellular organisms reproduce asexually, most multicellular eukaryotes are obligately sexual. This implies that there are strong barriers that prevent the origin or maintenance of asexuality arising from an obligately sexual ancestor. By studying rare asexual animal species we can gain a better understanding of the circumstances tha...

Antagonistic interactions drive host–virus evolutionary arms races, which often manifest as recurrent amino acid changes (i.e., positive selection) at their protein–protein interaction interfaces. Here, we investigated whether combinatorial mutagenesis of positions under positive selection in a host antiviral protein could enhance its restrictive p...

Natural selection works best when the two alleles in a diploid organism are transmitted to offspring at equal frequencies. Despite this, selfish loci known as meiotic drivers that bias their own transmission into gametes are found throughout eukaryotes. Drive is thought to be a powerful evolutionary force, but empirical evolutionary analyses of dri...

Natural selection works best when the two alleles in a diploid organism are transmitted to offspring at equal frequencies. Despite this, selfish loci known as meiotic drivers that bias their own transmission into gametes are found throughout eukaryotes. Drive is thought to be a powerful evolutionary force, but empirical evolutionary analyses of dri...

Eukaryotic genomes must accomplish both compact packaging for genome stability and inheritance, as well as accessibility for gene expression. They do so using post-translational modifications of four ancient canonical histone proteins (H2A, H2B, H3, and H4) and by deploying histone variants with specialized chromatin functions. Some histone variant...

Eukaryotic genomes must accomplish the tradeoff between compact packaging for genome stability and inheritance, and accessibility for gene expression. They do so using post-translational modifications of four ancient canonical histone proteins (H2A, H2B, H3 and H4), and by deploying histone variants with specialized chromatin functions. While some...

ELife digest Animals, plants and fungi produce sex cells – known as gametes – when they are preparing to reproduce. These cells are made when cells containing two copies of every gene in the organism divide to produce new cells that each only have one copy of each gene. Therefore, a particular gene copy usually has a 50% chance of being carried by...

Ciliated protozoans perform extreme forms of programmed somatic DNA rearrangement during development. The model ciliate Tetrahymena thermophila removes 34% of its germline micronuclear genome from somatic macronuclei by excising thousands of internal eliminated sequences (IESs), a process that shares features with transposon excision. Indeed, piggy...

ELife digest Cell compartments called mitochondria are responsible for producing much of the energy that animal and plant cells need. Most of the proteins in mitochondria are produced from genes found in another compartment called the nucleus. However, some mitochondrial proteins are made from genes found in the mitochondria themselves. Unlike the...

Nuclear pore complexes (NPCs) emerged as nuclear transport channels in eukaryotic cells ∼1.5 billion years ago. While the primary role of NPCs is to regulate nucleo–cytoplasmic transport, recent research suggests that certain NPC proteins have additionally acquired the role of affecting gene expression at the nuclear periphery and in the nucleoplas...

Significance Codon bias, the unequal use of synonymous codons to encode amino acids, is known to influence protein expression. Our work finds that codon bias can limit the expression of Toll-like receptor 7, a receptor implicated in autoimmune diseases such as lupus. Surprisingly, we find that the improved protein production associated with codon o...

Viruses impose diverse and dynamic challenges on host defenses. Diversifying selection of codons and gene copy number variation are two hallmarks of genetic innovation in antiviral genes engaged in host-virus genetic conflicts. The myxovirus resistance (Mx) genes encode interferon-inducible GTPases that constitute a major arm of the cell-autonomous...

Identifiers for sequences used in this study. Genbank accession numbers for all Mx gene sequences used for the analyses in this study. (DOCX)

Significance Many pathogens use molecular mimicry to subvert key cellular processes of the host. RNA-dependent protein kinase (PKR), a member of the eukaryotic translation initiation factor 2α (eIF2α) kinase family, is an important component of innate immunity in vertebrates and has often been subjected to inhibition by viral mimicry. In this study...

Mammalian genomes comprise many active and fossilized retroelements. The obligate requirement for retroelement integration affords host genomes an opportunity to 'domesticate' retroelement genes for their own purpose, leading to important innovations in genome defense and placentation. While many such exaptations involve retroviruses, the L1TD1 gen...

Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins enco...

The human double-homeodomain retrogene DUX4 is expressed in the testis and epigenetically repressed in somatic tissues. Facioscapulohumeral muscular dystrophy (FSHD) is caused by mutations that decrease the epigenetic repression of DUX4 in somatic tissues and result in mis-expression of this transcription factor in skeletal muscle. DUX4 binds sites...

CpG methylation analysis of D4Z4 in D4Z4-2.5 and D4Z4-12.5 mice. Upper panel: Schematic draw of the regions within D4Z4 where CpG and histone methylation were interrogated. A–D) Methylation levels of individual CpGs in the first partial D4Z4 unit (A,B) or upstream of the DUX4 ORF (C,D) were analyzed in whole D4Z4-12.5 and D4Z4-2.5 embryos (E13,5) (...

In situ hybridization to detect DUX4 mRNA in D4Z4-2.5 mouse testis. Frozen sections of control mouse testes (A,D) and D4Z4-2.5 mouse testes (B–C, E–F) hybridized with antisense RNA probes for the 5′ (A–C) or 3′ (D–F) regions of human DUX4. C and F show magnifications of indicated regions in B and E respectively. Control testes show no staining, whe...

Intensity plot of array probes of C2C12+pCS2-DUX4 versus C2C12+pCS2. Normalized, log transformed mean intensities (triplicates) of C2C12+pCS2 are plotted against C2C12+pCS2-DUX4 per probe. Black dots indicate significantly deregulated probes. Circled probes indicate DUX4 activated genes, with very low intensities (≤7.5) in pCS2 transfected cells. (...

Luciferase reporter assays using a direct DUX4 target site. Normalized relative luciferase activity of the Nhlcr3 and 2810046L04Rik bidirectional DUX4 binding site in forward (Fw) and reverse (Rev) orientation in the absence (pCS2) or presence (pCS2-DUX4) of DUX4. Below a schematic overview of the DUX4 binding site is shown. All values are first no...

DUX4 Expression analysis in muscles of D4Z4-2.5 and D4Z4-12.5 mice. DUX4 RT-PCR analysis in duplicate of muscle tissues of adult A) D4Z4-2.5 (n = 3) and B) D4Z4-12.5 (n = 3) mice in Hea = Heart, Dia = Diaphragm, Pec = Pectoralis Mas = Masseter, Orb = Orbicularis oris, Qua = Quadriceps, TA = Tibialis anterior, Gas = Gastrocnemius, Ton = Tongue. Hprt...

DUX4 Expression analysis in non-muscle tissue of D4Z4-2.5 and D4Z4-12.5 mice. DUX4 RT-PCR analysis in duplicate of non-muscle tissues of adult A) D4Z4-2.5 (n = 3) and B) D4Z4-12.5 (n = 3) mice in Tes = Testis, Ute = Uterus, Ova = Ovarium, Eye, Cer = Cerebellum, Spl = Spleen, Kid = Kidney, Liv = Liver. Hprt was used as control for RNA integrity. C)...

Consensus binding site sequence sequences of DUX4 at different genetic contexts. Position weight matrices of the DUX4 consensus binding sequence at A) unique binding sites, B) MaLR retrotransposons and C) L1 retrotransposons. The core double homeobox is conserved at all regions, flanking nucleotides show context specific variation. (TIF)

Distribution of DUX4 binding sites in the mouse genome. Relative distribution of ChIP peaks is displayed as the number of peaks per kb of total genomic sequence for each context. DUX4 shows a slight promoter bias as seen for transcription factors, but not for DUX4 in human myoblasts. (TIF)

Expression analysis of the DUX4 target Wfdc3 in E9,5 embryos. Wfdc3 shows significant upregulation in D4Z4-2.5 embryos compared to wt controls (n = 6). Expression levels are normalized to the mouse reference gene Hprt and are plotted as the mean ± SEM. Asterisks indicate p<0.05 according to a student's t-test. (TIF)

DUX4 induced deregulated genes overlapping between C2C12 and human myoblasts. (XLS)

Unique DUX4 binding sites in transposable elements in C2C12 myoblasts. (XLS)

DUX4 binding sites in transposable elements in C2C12 myoblasts. (XLS)

Overview of the histological and functional tests performed to investigate muscle integrity and performance in D4Z4-2.5 mice. (XLS)

List of primers and corresponding sequences. (PDF)

Supporting Materials and Methods and References. (PDF)

Deregulated genes in response to ectopic DUX4 expression in C2C12 myoblasts. (XLS)

Keratitis in D4Z4-2.5 mice at different ages. Representative pictures of eyes of WT (A,C,E,G) and D4Z4-2.5 (B,D,F,H) mice at 11 weeks (A&B), 17 weeks (C&D), 27 weeks (E&F) and 1,5 years (G&H) of age. (TIF)

Identified direct targets of DUX4 in C2C12 myoblasts. (PDF)

Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric regi...

Innate immune detection of nucleic acids is important for initiation of antiviral responses. Detection of intracellular DNA activates STING-dependent type I interferons (IFNs) and the ASC-dependent inflammasome. Certain members of the AIM2-like receptor (ALR) gene family contribute to each of these pathways, but most ALRs remain uncharacterized. He...

Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was...

Figure S1.RD cells infected with ZNF238 and RUNX1 viruses increase expression of the appropriate factor. (A) RT-PCR for ZNF238 in RD cells infected with either a control virus or the ZNF238-containing virus. TIMM17b is used as a loading control. (B) Western blot using whole cell lysates for RUNX1 in control and RUNX1 virus infected RD cells. The bl...

Table S1.Primer and oligonucleotide sequences.

Figure S2.RUNX1 differentiates alveolar subtype RMS cells. (A) Western blots on whole cell lysates from RhJT cells infected with either a RUNX1-expressing or control virus. MHC is myosin heavy chain, a marker of myogenesis, and alpha-tubulin is the loading control. Blots were serially stripped and reprobed, and bands confirmed to be of the correct...

Table S4.Select potential regulators of myogenesis affected by RUNX1, ZNF238, and miR-206.

Table S2.miRNA changes in response to MD~E expression in RD cells.

Table S3.Top GO categories of genes regulated by RUNX1, ZNF238, and miR-206.

Figure S9.MSC inhibits the activation of the miR-206 reporter by the forced MD~E dimer. Luciferase assay results in RD cells using the miR-206 promoter reporter with constant amounts of MyoD and E12 introduced individually or as the forced dimer, in the presence of varying amounts of co-transfected MSC. - indicates no MSC was added, 1x indicates th...

Figure S3.Differential effects on miRNA expression by the forced MD~E dimer. (A) miRNA northern blot for miR-199a* (also known as miR-199a-5p) from RD cells either transduced with a control or MD~E virus. (B) miRNA northern blot for miR-29b as in panel A.

Figure S5.MyoD activity increases ZNF238 expression during myogenic conversion. 10T1/2 fibroblast cells expressing an estradiol-inducible version of MyoD were induced to undergo myogenesis by addition of beta-estradiol to the culture medium. RNA was taken at the indicated times under indicated conditions and qPCR performed to quantitate the relativ...

Figure S7.MSC occupancy in the miR-206 promoter diminishes with MD~E differentiation. ChIP for MSC in the miR-206 promoter in RD cells either transduced with empty virus (Control), or differentiated through the expression of the forced MD~E protein dimer (MD~E). Values are the means ± standard deviation of two independent experiments. Corrected rel...

Figure S11.MD~E expression results in greater myotube formation than MD~E2/5 expression. (A) Light microscopy images of RD cells transduced with either control virus (Control) or virus expressing either the MD~E or MD~E2/5 forced protein dimers and allowed to differentiate for 24 h. Arrows indicate representative cells that have appeared to form my...

Figure S4.miR-206 affects alveolar subtype RMS cells and miR-133b does not share its effects. (A) Immunostains for MHC in RhJT cells transfected with either a pre-miR-206 or control construct. DAPI stains all nuclei. (B) Stains as in A after transfection of RD cells with pre-miR-133b or a control construct. (C) qPCR for CKM in RD cells treated as i...

Figure S6.The miR-206 promoter in RD cells is bound by MyoD and has acetylated histone H4. (A) ChIP for MyoD in RD cells in differentiation media shows MyoD enrichment upstream of miR-206, compared to a control locus at a non-expressed gene (hemoglobin beta). (B) Site-specific ChIPs in RD cells for acetylated histone H4, at hemoglobin beta (control...

Figure S10.Strong miR-206 activation is dependent on multiple E-boxes. Luciferase assay results in RD cells with transient transfection as indicated using the miR-206 promoter and a reporter in which the E-box exhibiting the peak of MyoD occupancy in RD cells (indicated by the red marker in Figure 5C) has been mutated and eliminated as a site of bH...

Figure S8.In vitro assessment of MyoD and MSC binding in the miR-206 promoter. Electrophoretic mobility shift assays were performed using in vitro translated proteins as indicated and probes that represent the DNA sequence under either the E-box occupied most prominently by MyoD in RD cells as assessed by ChIP-seq results (MyoD-binding E-box) or th...

Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The gene...

Figure showing that most O/E sites predicted using MatInspector's less stringent parameters are evolutionarily conserved. The solid gray line shows all mouse O/E sites predicted using MatInspector's less stringent parameters. For reference we include a dotted gray line showing all mouse O/E sites predicted using MatInspector's default parameters. A...

Table listing olfactory receptor genes and pseudogenes in the July 2007 mouse genome assembly. See Methods for details of how gene names were determined.

Table summarizing statistical tests on matrix families for 200-bp promoter region (less stringent MatInspector parameters). Results of our statistical tests for enrichment and conservation for all matrix families after masking O/E sites and TATA boxes using less stringent MatInspector parameters. See legend to Table 1.

Table summarizing statistical tests on matrix families for 500-bp promoter region (less stringent MatInspector parameters). See legend to Additional File 6.

Summary of statistical tests for 500-bp promoter region. See legend to Table 1. This table gives equivalent statistics for a larger putative promoter region comprising 500bp before the TSS. Binomial tests here show comparison with the preceding 500-bp region.

Table summarizing statistical tests on matrix families for 500-bp promoter region (default MatInspector parameters). See legend to Additional File 5.

Table summarizing statistical tests on individual matrices for 500-bp promoter region (default MatInspector parameters). See legend to Additional File 10.

Table listing TSS locations and data sources. This table shows all TSS locations we collected from a high-throughput RACE study [20], our hybridization-based cDNA screen [13] and various other RACE experiments performed on smaller numbers of ORs [6,14,17,18,52,85-87]. For some ORs, more than experiment defines a TSS (so there are multiple rows for...

Table summarizing statistical tests on individual matrices for 200-bp promoter region (less stringent MatInspector parameters). Results of our statistical tests for enrichment and conservation for individual matrices after masking O/E sites and TATA boxes using less stringent MatInspector parameters. See legend to Table 1 and Additional File 10.

Table summarizing statistical tests on individual matrices for 500-bp promoter region (less stringent MatInspector parameters). See legend to Additional File 11.

Figure showing enrichment of transcription factor binding sites 200 bp before TSS using less stringent MatInspector parameters. These plots follow the same layout as those in Figure 2 but use transcription factor site predictions made using MatInspector with less stringent parameters (see Methods).

Table summarizing statistical tests on matrix families for 200-bp promoter region (default MatInspector parameters). Results of our statistical tests for enrichment and conservation for all matrix families after masking O/E sites and TATA boxes using default MatInspector parameters. See legend to Table 1.

Table summarizing statistical tests on individual matrices for 200-bp promoter region (default MatInspector parameters). Results of our statistical tests for enrichment and conservation for individual matrices after masking O/E sites and TATA boxes using less stringent MatInspector parameters. See legend to Table 1. In addition, for selected matric...

Mammalian olfactory receptors (ORs) are subject to a remarkable but poorly understood regime of transcriptional regulation, whereby individual olfactory neurons each express only one allele of a single member of the large OR gene family. We performed a rigorous search for enriched sequence motifs in the largest dataset of OR promoter regions analyz...

The partial DNA sequences of nine of the top ten V1R genes selected in our screen of Perlegen SNPs. These were rejected as having few or no fixed differences between PWD and WSB. (0.05 MB TXT)

Vmn1r67 amino acid sequences used in constructing Fig. 3. (0.00 MB TXT)

The five M. m. domesticus and five M. m. musculus Vmn1r71 gene sequences that contributed to the reduced data set shown in Figure 1B. (0.01 MB TXT)

Synonymous and nonsynonymous sites in Vmn1r67. Synonymous and nonsynonymous sites where apparent homoplasy was discovered when the species tree was used instead of the gene tree in CODEML analysis. (0.00 MB TXT)

The five M. m. domesticus and five M. m. musculus Vmn1r67 gene sequences that contributed to the reduced data set shown in Figure 1A. (0.01 MB TXT)

Vmn1r67 gene sequences used to construct the gene tree for CODEML analysis. (0.01 MB TXT)

Raw data from the Perlegen screen. Screen of the Perlegen SNP data on V1R genes ranked from most PWD-WSB SNPs to least. (0.05 MB XLS)

Assortative mating, a potentially efficient prezygotic reproductive barrier, may prevent loss of genetic potential by avoiding the production of unfit hybrids (i.e., because of hybrid infertility or hybrid breakdown) that occur at regions of secondary contact between incipient species. In the case of the mouse hybrid zone, where two subspecies of M...

We report an evolutionary analysis of the V1R gene family across 37 mammalian genomes. V1Rs comprise one of three chemosensory receptor families expressed in the vomeronasal organ, and contribute to pheromone detection. We first demonstrate that Trace Archive data can be used effectively to determine V1R family sizes and to obtain sequences of most...

Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array comparative genomic hybridization (ar...

DNA methylation is a major epigenetic modification important for regulating gene expression and suppressing spurious transcription. Most methods to scan the genome in different tissues for differentially methylated sites have focused on the methylation of CpGs in CpG islands, which are concentrations of CpGs often associated with gene promoters. He...

Figure S4. Hierarchical clustering of methylation profiles from 45 fractionated DNA samples from 15 tissue samples. GC-normalized ratios were clustered using Manhattan distances and the Ward method of hierarchical clustering using R's hclust function. The dendrogram demonstrates that there is tight correlation within each set of triplicate samples...

Figure S2. Scatter plots are displayed above the diagonal to illustrate pairwise comparisons between results of different methylation profiling microarray experiments performed using various brain tissue samples. The corresponding Pearson R2 correlation coefficients are shown below the diagonal. This figure includes three replicate arrays for each...

Figure S6. Reproducibility of methylation profiles across three experiments in which heart DNA is compared with spleen using tissue from the male donor. DNA was extracted from a single heart and single spleen tissue sample, and each DNA preparation was then divided into aliquots that were independently processed through HpaII digestion, size select...

Figure S3. Scatter plots are displayed above the diagonal to illustrate pairwise comparisons between results of different methylation profiling microarray experiments performed using various tissues from two donors. Here one representative replicate of each tissue from each donor is included in the pairwise comparison dataset. The corresponding Pea...

Table S1. Replicates of test and spleen reference paired for each array.

Figure S1. Scatter plots are displayed above the diagonal to illustrate pairwise comparisons between results of different methylation profiling microarray experiments. The corresponding Pearson R2 correlation coefficients are shown below the diagonal. This figure includes three replicate arrays each for various tissue samples from each of two donor...

Figure S5. Chromosome 1 G-banding, GC%, gene density, and HpaII site distribution. The G-banding pattern of chromosome 1 is aligned to plots of (1) of the percentage of G or C nucleotides in each array clone as a function of the clone's position along the chromosome, (2) of the number of start sites of RefSeq genes in non-overlapping windows of 1 M...

Figure S7. Enlarged view of clones on the array around the region containing the ryanodine cardiac receptor 2 gene (RYR2). Relative positions of bacterial artificial chromosomes (BACs) covering the region flanking RP11-47A4 (AL391809) and their corresponding mean log2 ratios (dotted lines are at ± 1 standard error of the mean) in six heart-versus-s...

Figure S8. Methylation status of CpGs in RP11-47A4 (AL391809), which contains the RYR2 gene, as determined by sequencing of PCR products amplified after bisulfite conversion of unmethylated cytosines to uracil. These data are summarized in Figure 6. Here, the raw data are provided for each sequenced amplicon from heart or spleen. Filled squares rep...

Figure S9. Expression ratios tend to be higher for genes whose 5' ends fall in regions of lower methylation (that is, in bacterial artificial chromosomes (BACs) with higher methylation array ratios) than those in regions of higher methylation. Data are presented as in Figure 7, but here BACs are classified in the 'High' and 'Low' categories using a...

Figure S10. Methylation profile in which two independently processed aliquots of DNA isolated from medulla tissue from the same female donor are directly compared. The log2 ratios for chromosome 1 clones are indicated at their relative genomic position, with the large gap representing the centromere and pericentromeric repeats in 1p11–1q21. The hor...