Elisabeth Sundström

• PhD Molecular Genetics
• Researcher at Uppsala University

Current knowledge of cancer genomics remains biased against noncoding mutations. To systematically search for regulatory noncoding mutations, we assessed mutations in conserved positions in the genome under the assumption that these are more likely to be functional than mutations in positions with low conservation. To this end, we use whole-genome...

Protein-coding differences between species often fail to explain phenotypic diversity, suggesting the involvement of genomic elements that regulate gene expression such as enhancers. Identifying associations between enhancers and phenotypes is challenging because enhancer activity can be tissue-dependent and functionally conserved despite low seque...

Annotating coding genes and inferring orthologs are two classical challenges in genomics and evolutionary biology that have traditionally been approached separately, limiting scalability. We present TOGA (Tool to infer Orthologs from Genome Alignments), a method that integrates structural gene annotation and orthology inference. TOGA implements a d...

Human accelerated regions (HARs) are conserved genomic loci that evolved at an accelerated rate in the human lineage and may underlie human-specific traits. We generated HARs and chimpanzee accelerated regions with an automated pipeline and an alignment of 241 mammalian genomes. Combining deep learning with chromatin capture experiments in human an...

The precise pattern and timing of speciation events that gave rise to all living placental mammals remain controversial. We provide a comprehensive phylogenetic analysis of genetic variation across an alignment of 241 placental mammal genome assemblies, addressing prior concerns regarding limited genomic sampling across species. We compared neutral...

Conserved genomic sequences disrupted in humans may underlie uniquely human phenotypic traits. We identified and characterized 10,032 human-specific conserved deletions (hCONDELs). These short (average 2.56 base pairs) deletions are enriched for human brain functions across genetic, epigenomic, and transcriptomic datasets. Using massively parallel...

We reconstruct the phenotype of Balto, the heroic sled dog renowned for transporting diphtheria antitoxin to Nome, Alaska, in 1925, using evolutionary constraint estimates from the Zoonomia alignment of 240 mammals and 682 genomes from dogs and wolves of the 21st century. Balto shares just part of his diverse ancestry with the eponymous Siberian hu...

Species persistence can be influenced by the amount, type, and distribution of diversity across the genome, suggesting a potential relationship between historical demography and resilience. In this study, we surveyed genetic variation across single genomes of 240 mammals that compose the Zoonomia alignment to evaluate how historical effective popul...

Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription fac...

Chronic kidney disease (CKD) affects 10% of the human population, with only a small fraction genetically defined. CKD is also common in dogs and has been diagnosed in nearly all breeds, but its genetic basis remains unclear. Here, we performed a Bayesian mixed model genome-wide association analysis for canine CKD in a boxer population of 117 canine...

Canine atopic dermatitis is an inflammatory skin disease with clinical similarities to human atopic dermatitis. Several dog breeds are at increased risk for developing this disease but previous genetic associations are poorly defined. To identify additional genetic risk factors for canine atopic dermatitis, we here apply a Bayesian mixture model ad...

Atlantic Halibut (Hippoglossus hippoglossus) has a X/Y genetic sex determination system, but the sex determining factor is not known. We produced a high-quality genome assembly from a male and identified parts of chromosome 13 as the Y chromosome due to sequence divergence between sexes and segregation of sex genotypes in pedigrees. Linkage analysi...

We present GSD_1.0, a high-quality domestic dog reference genome with chromosome length scaffolds and contiguity increased 55-fold over CanFam3.1. Annotation with generated and existing long and short read RNA-seq, miRNA-seq and ATAC-seq, revealed that 32.1% of lifted over CanFam3.1 gaps harboured previously hidden functional elements, including pr...

Atlantic Halibut (Hippoglossus hippoglossus) has a X/Y genetic sex determination system, but the sex determining factor is not known. We produced a high-quality genome assembly and identified parts of chromosome 13 as the Y chromosome due to sequence divergence between sexes and segregation of sex genotypes in pedigrees. Linkage analysis revealed t...

We present GSD_1.0, a novel high-quality domestic dog reference genome with chromosome length scaffolds and gap number reduced 41-fold, from 23,836 to 585. Annotation with novel and existing long and short read RNA-seq, miRNA-seq and ATAC-seq, revealed that 32.1% of closed gaps harboured previously hidden functional elements, including promoters, g...

Here we present a new high-quality canine reference genome with gap number reduced 41-fold, from 23,836 to 585. Analysis of existing and novel data, RNA-seq, miRNA-seq and ATAC-seq, revealed a large proportion of these harboured previously hidden elements, including genes, promoters and miRNAs. Short-read dark regions were detected, and genomic reg...

Background: Glioblastoma (GBM) has one of the worst 5-year survival rates of all cancers. While genomic studies of the disease have been performed, alterations in the non-coding regulatory regions of GBM have largely remained unexplored. We apply whole-genome sequencing (WGS) to identify non-coding mutations, with regulatory potential in GBM, unde...

A single nucleotide substitution in the third intron of insulin-like growth factor 2 (IGF2) is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of IGF2 expression in pig skeletal muscle. Here, we investigat...

Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we sho...

Primer sequences used to investigate molecular mechanisms of Sex-linked barring mutations. (DOCX)

B2/N male feathers from different body regions. (TIF)

Caspase staining of different parts of the feather follicle for chickens carrying three different CDKN2A genotypes. No pre-apoptotic cells were observed in any feather region apart from the pulp. (TIF)

Far-UV CD spectra of (A) MDM2204-298, ARF1-14WT and ARF1-14WT/MDM2204-298 at different concentrations, (B) MDM2204-298, ARF1-14V9D/MDM2204-298 and ARF1-14V9D at different concentrations and (C) MDM2204-298, ARF1-14R10C and ARF1-14R10C/MDM2204-298 at different peptide concentrations. (TIF)

In situ hybridization signal in chicken feather follicles obtained with a CDKN2A probe in different CDKN2A genotypes. (DOCX)

Phenotype of chicks at hatch with different CDKN2A genotypes: (A) N/N, (B) B0/N and (C) B2/N allele. The arrow marks the characteristic white spot associated with Sex-linked barring. (TIF)

Relative expression of downstream targets of p53 (CDKN1A, DRAM1 and PHLDA3) as well as four members of the 14-3-3 gene family involved in cell cycle regulation (YWHAB, YWHAE, YWHAZ and SFN). Significant differences in average relative gene expression between B0/- and N/- feathers were only observed for PHLDA3 and YWHAB. Expression data was normaliz...

Isothermal titration calorimetry experiments in which (A) ARF peptides WT, (B) V9D and (C) R10C were titrated into 100 μM MDM2204-298. Top panels, peaks resulting from heat of dilution upon titration of 1.27 mM into 100 μM. Middle panels, uncorrected peaks for titration of ARF peptides into MDM2204-298. Bottom panels, integrated heat data corrected...

Average number of MITF+, MART1+, TYR+ and CDKN2A+ cells/mm2 in different parts of the feather in different genotypes. Significant differences from the value obtained for N/N are indicated by stars (One-way ANOVA, Tukey’s multi-comparison post-hoc test; * P<0.05, ** P<0.01, *** P<0.001). (DOCX)

Dun is a wild-type coat color in horses characterized by pigment dilution with a striking pattern of dark areas termed primitive markings. Here we show that pigment dilution in Dun horses is due to radially asymmetric deposition of pigment in the growing hair caused by localized expression of the T-box 3 (TBX3) transcription factor in hair follicle...

Background: Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with...

The white spotting locus (S) in dogs is colocalized with the MITF (microphtalmia-associated transcription factor) gene. The phenotypic effects of the four S alleles range from solid colour (S) to extreme white spotting (sw). We have investigated four candidate mutations associated with the sw allele, a SINE insertion, a SNP at a conserved site and...

ZBED6 is a recently discovered transcription factor, unique to placental mammals, that has evolved from a domesticated DNA transposon. It acts as a repressor at the IGF2 locus. Here we show that ZBED6 acts as a transcriptional modulator in mouse myoblast cells, where more than 700 genes were differentially expressed after Zbed6-silencing. The most...

Aim Investigate the role of ZBED6 during the differentiation of myoblasts and how it affects the expression of myogenic genes Materials and methods Background - ZBED6 was recently discovered as a repressor of IGF2 based on the characterization of a mutation in intron 3 of IGF2 in pigs 1 . - This mutation disrupts the binding of ZBED6 and leads to a...

The Grey horse phenotype, caused by a 4.6 kb duplication in Syntaxin 17, is strongly associated with high incidence of melanoma. In contrast to most human melanomas with an early onset of metastasis, the Grey horse melanomas have an extended period of benign growth, after which 50% or more eventually undergo progression and may metastasize. In effo...

The dominant phenotype of greying with age in horses, caused by a 4.6-kb duplication in intron 6 of STX17, is associated with a high incidence of melanoma and vitiligo-like skin depigmentation. However, the progressive greying and the incidence of melanoma, vitiligo-like depigmentation, and amount of speckling in these horses do not follow a simple...

Background Double-hit lymphoma is a complex and highly aggressive sub-type of B-cell lymphoma, which has recently been classified and is an area of active research interest due to the poor prognosis for patients with this disease. It is characterized by the presence of both an activating MYC chromosomal translocation and a simultaneous additional o...

Figure S3. Detail of an insertion of extragenous DNA and deletion of material on chromosome 20. This rearrangement was predicted by sequencing and undetected by conventional methods, but yet confirmed by PCR.

Background Greying with age in horses is an autosomal dominant trait, associated with loss of hair pigmentation, melanoma and vitiligo-like depigmentation. We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype. The aims of this study were to investigate if the duplication in Grey horses shows copy number variation...

The late greying Connemara horses are heterozygous for the STX17 duplication.Copy number assay for the STX17 duplication from tests with four different probes using constitutional DNA from the late greying Connemara horses SP1, SP2, SP3. The sample denoted ‘Calibr’ is a g/g individual with a known copy number of 2, used as a calibrator in the IN, O...

Primer sequences used for characterization of the region harbouring the Grey mutation in horses.

Lack of copy number variation outside and over the 5’breakpoint of the STX17 duplication in constitutional DNA from Grey horses.94 Grey Lipizzaner horses and one calibrator sample with a known copy number of 2 were included in the analysis. OUT = outside the duplicated sequence and BP n = the border between the 5’flanking sequence and the 5’end of...

Greying with age in horses is an autosomal dominant trait, characterized by hair greying, high incidence of melanoma and vitiligo-like depigmentation. Previous studies have revealed that the causative mutation for this phenotype is a 4.6-kb intronic duplication in STX17 (Syntaxin 17). By using reporter constructs in transgenic zebrafish, we show th...

A captive breeding programme for the Fennoscandian Arctic fox (Vulpes lagopus; syn. Alopex lagopus) failed due to fatal encephalitis. The aim of this study was to identify the causative agent. Viral nucleic acid was detected by PCR and in situ hybridization in the brain of affected foxes. The results suggest that a herpesvirus might be the causativ...

A DNA transposon integrated into -the genome of a primitive mammal some 200 million years ago and, millions of years later, it evolved an essential function in the common ancestor of all placental mammals. This protein, now named ZBED6, was recently discovered because a mutation disrupting one of its binding sites, in an intron of the IGF2 gene, ma...

Sex-linked barring, a common plumage colour found in chickens, is characterized by black and white barred feathers. Previous studies have indicated that the white bands are caused by an absence of melanocytes in the feather follicle during the growth of this region. Here, we show that Sex-linked barring is controlled by the CDKN2A/B locus, which en...

In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpre...

Ever since man domesticated the first wild animals several thousand years ago, many species have been living in close relationship with humans, being objects for our requests and wishes about any kind of phenotypic traits. As a result, we have by selective breeding created a fascinating spectrum of phenotypes within most species we have domesticate...