Biology subjects

Salama, S.

Publications and source records attributed to Salama, S..

3 recordsLinked to original sources

bioRxiv2018

The UCSC Repeat Browser allows discovery and visualization of evolutionary conflict across repeat families

BackgroundNearly half the human genome consists of repeat elements, most of which are retrotransposons, and many of these sequences play important biological roles. However repeat elements pose several unique challenges to current bioinformatic analyses and visualization tools, as short repeat sequences can map to multiple genomic loci resulting in their misclassification and misinterpretation. In fact, sequence data mapping to repeat elements are often discarded from analysis pipelines. Therefore, there is a continued need for standardized tools and techniques to interpret genomic data of repeats. ResultsWe present the UCSC Repeat Browser, which consists of a complete set of human repeat reference sequences derived from the gold standard repeat database RepeatMasker. The UCSC Repeat Browser contains mapped annotations from the human genome to these references, and presents all of them as a comprehensive interface to facilitate work with repetitive elements. Furthermore, it provides processed tracks of multiple publicly available datasets of biological interest to the repeat community, including ChIP-SEQ datasets for KRAB Zinc Finger Proteins (KZNFs) - a family of proteins known to bind and repress certain classes of repeats. Here we show how the UCSC Repeat Browser in combination with these datasets, as well as RepeatMasker annotations in several non-human primates, can be used to trace the independent trajectories of species-specific evolutionary conflicts. ConclusionsThe UCSC Repeat Browser allows easy and intuitive visualization of genomic data on consensus repeat elements, circumventing the problem of multi-mapping, in which sequencing reads of repeat elements map to multiple locations on the human genome. By developing a reference consensus, multiple datasets and annotation tracks can easily be overlaid to reveal complex evolutionary histories of repeats in a single interactive window. Specifically, we use this approach to retrace the history of several primate specific LINE-1 families across apes, and discover several species-specific routes of evolution that correlate with the emergence and binding of KZNFs.

genomics↗

bioRxiv2018

KRAB Zinc Finger Proteins coordinate across evolutionary time scales to battle retroelements

KRAB Zinc Finger Proteins (KZNFs) are the largest and fastest evolving family of human transcription factors1,2. The evolution of this protein family is closely linked to the tempo of retrotransposable element (RTE) invasions, with specific KZNF family members demonstrated to transcriptionally repress specific families of RTEs3,4. The competing selective pressures between RTEs and the KZNFs results in evolutionary arms races whereby KZNFs evolve to recognize RTEs, while RTEs evolve to escape KZNF recognition5. Evolutionary analyses of the primate-specific RTE family L1PA and two of its KZNF binders, ZNF93 and ZNF649, reveal specific nucleotide and amino changes consistent with an arms race scenario. Our results suggest a model whereby ZNF649 and ZNF93 worked together to target independent motifs within the L1PA RTE lineage. L1PA elements eventually escaped the concerted action of this KZNF \"team\" over [~]30 million years through two distinct mechanisms: a slow accumulation of point mutations in the ZNF649 binding site and a rapid, massive deletion of the entire ZNF93 binding site.

evolutionary biology↗

bioRxiv2016

Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression

About 16% of breast cancers fall into a clinically aggressive category designated triple negative (TNBC) due to a lack of ERBB2, estrogen receptor and progesterone receptor expression1-3. The mutational spectrum of TNBC has been characterized as part of The Cancer Genome Atlas (TCGA)4; however, snapshots of primary tumors cannot reveal the mechanisms by which TNBCs progress and spread. To address this limitation we initiated the Intensive Trial of OMics in Cancer (ITOMIC)-001, in which patients with metastatic TNBC undergo multiple biopsies over space and time5. Whole exome sequencing (WES) of 67 samples from 11 patients identified 426 genes containing multiple distinct single nucleotide variants (SNVs) within the same sample, instances we term Multiple SNVs affecting the Same Gene and Sample (MSSGS). We find that >90% of MSSGS result from cis-compound mutations (in which both SNVs affect the same allele), that MSSGS comprised of SNVs affecting adjacent nucleotides arise from single mutational events, and that most other MSSGS result from the sequential acquisition of SNVs. Some MSSGS drive cancer progression, as exemplified by a TNBC driven by FGFR2(S252W;Y375C). MSSGS are more prevalent in TNBC than other breast cancer subtypes and occur at higher-than-expected frequencies across TNBC samples within TCGA. MSSGS may denote genes that play as yet unrecognized roles in cancer progression.

clinical trials↗