Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘Wellcome trust sanger institute’


Bioinformatic Tools for Cancer Mutational Analysis: COSMIC and Beyond

Curator: Stephen J. Williams, Ph.D.

Updated 04/27/2019

Signatures of Mutational Processes in Human Cancer (from COSMIC)

From The COSMIC Database

summary_circos_cosmic_38_380

The genomic landscape of cancer. The COSMIC database has a fully curated and annotated database of recurrent genetic mutations founds in various cancers (data taken form cancer sequencing projects). For interactive map please go to the COSMIC database here: http://cancer.sanger.ac.uk/cosmic

 

 

Somatic mutations are present in all cells of the human body and occur throughout life. They are the consequence of multiple mutational processes, including the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, enzymatic modification of DNA and defective DNA repair. Different mutational processes generate unique combinations of mutation types, termed “Mutational Signatures”.

In the past few years, large-scale analyses have revealed many mutational signatures across the spectrum of human cancer types [Nik-Zainal S. et al., Cell (2012);Alexandrov L.B. et al., Cell Reports (2013);Alexandrov L.B. et al., Nature (2013);Helleday T. et al., Nat Rev Genet (2014);Alexandrov L.B. and Stratton M.R., Curr Opin Genet Dev (2014)]. However, as the number of mutational signatures grows the need for a curated census of signatures has become apparent. Here, we deliver such a resource by providing the profiles of, and additional information about, known mutational signatures.

The current set of mutational signatures is based on an analysis of 10,952 exomes and 1,048 whole-genomes across 40 distinct types of human cancer. These analyses are based on curated data that were generated by The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and a large set of freely available somatic mutations published in peer-reviewed journals. Complete details about the data sources will be provided in future releases of COSMIC.

The profile of each signature is displayed using the six substitution subtypes: C>A, C>G, C>T, T>A, T>C, and T>G (all substitutions are referred to by the pyrimidine of the mutated Watson–Crick base pair). Further, each of the substitutions is examined by incorporating information on the bases immediately 5’ and 3’ to each mutated base generating 96 possible mutation types (6 types of substitution ∗ 4 types of 5’ base ∗ 4 types of 3’ base). Mutational signatures are displayed and reported based on the observed trinucleotide frequency of the human genome, i.e., representing the relative proportions of mutations generated by each signature based on the actual trinucleotide frequencies of the reference human genome version GRCh37. Note that only validated mutational signatures have been included in the curated census of mutational signatures.

Additional information is provided for each signature, including the cancer types in which the signature has been found, proposed aetiology for the mutational processes underlying the signature, other mutational features that are associated with each signature and information that may be relevant for better understanding of a particular mutational signature.

The set of signatures will be updated in the future. This will include incorporating additional mutation types (e.g., indels, structural rearrangements, and localized hypermutation such as kataegis) and cancer samples. With more cancer genome sequences and the additional statistical power this will bring, new signatures may be found, the profiles of current signatures may be further refined, signatures may split into component signatures and signatures

See their COSMIC tutorial page here for instructional videos

Updated News: COSMIC v75 – 24th November 2015

COSMIC v75 includes curations across GRIN2A, fusion pair TCF3-PBX1, and genomic data from 17 systematic screen publications. We are also beginning a reannotation of TCGA exome datasets using Sanger’s Cancer Genome Project analyis pipeline to ensure consistency; four studies are included in this release, to be expanded across the next few releases. The Cancer Gene Census now has a dedicated curator, Dr. Zbyslaw Sondka, who will be focused on expanding the Census, enhancing the evidence underpinning it, and developing improved expert-curated detail describing each gene’s impact in cancer. Finally, as we begin to streamline our ever-growing website, we have combined all information for each gene onto one page and simplified the layout and design to improve navigation

may be found in cancer types in which they are currently not detected.

mutational signatures across human cancer

Mutational signatures across human cancer

Patterns of mutational signatures [Download signatures]

 COSMIC database identifies 30 mutational signatures in human cancer

Please goto to COSMIC site to see bigger .png of mutation signatures

Signature 1

Cancer types:

Signature 1 has been found in all cancer types and in most cancer samples.

Proposed aetiology:

Signature 1 is the result of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine.

Additional mutational features:

Signature 1 is associated with small numbers of small insertions and deletions in most tissue types.

Comments:

The number of Signature 1 mutations correlates with age of cancer diagnosis.

Signature 2

Cancer types:

Signature 2 has been found in 22 cancer types, but most commonly in cervical and bladder cancers. In most of these 22 cancer types, Signature 2 is present in at least 10% of samples.

Proposed aetiology:

Signature 2 has been attributed to activity of the AID/APOBEC family of cytidine deaminases. On the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems, a role for APOBEC1, APOBEC3A and/or APOBEC3B in human cancer appears more likely than for other members of the family.

Additional mutational features:

Transcriptional strand bias of mutations has been observed in exons, but is not present or is weaker in introns.

Comments:

Signature 2 is usually found in the same samples as Signature 13. It has been proposed that activation of AID/APOBEC cytidine deaminases is due to viral infection, retrotransposon jumping or to tissue inflammation. Currently, there is limited evidence to support these hypotheses. A germline deletion polymorphism involving APOBEC3A and APOBEC3B is associated with the presence of large numbers of Signature 2 and 13 mutations and with predisposition to breast cancer. Mutations of similar patterns to Signatures 2 and 13 are commonly found in the phenomenon of local hypermutation present in some cancers, known as kataegis, potentially implicating AID/APOBEC enzymes in this process as well.

Signature 3

Cancer types:

Signature 3 has been found in breast, ovarian, and pancreatic cancers.

Proposed aetiology:

Signature 3 is associated with failure of DNA double-strand break-repair by homologous recombination.

Additional mutational features:

Signature 3 associates strongly with elevated numbers of large (longer than 3bp) insertions and deletions with overlapping microhomology at breakpoint junctions.

Comments:

Signature 3 is strongly associated with germline and somatic BRCA1 and BRCA2 mutations in breast, pancreatic, and ovarian cancers. In pancreatic cancer, responders to platinum therapy usually exhibit Signature 3 mutations.

Signature 4

Cancer types:

Signature 4 has been found in head and neck cancer, liver cancer, lung adenocarcinoma, lung squamous carcinoma, small cell lung carcinoma, and oesophageal cancer.

Proposed aetiology:

Signature 4 is associated with smoking and its profile is similar to the mutational pattern observed in experimental systems exposed to tobacco carcinogens (e.g., benzo[a]pyrene). Signature 4 is likely due to tobacco mutagens.

Additional mutational features:

Signature 4 exhibits transcriptional strand bias for C>A mutations, compatible with the notion that damage to guanine is repaired by transcription-coupled nucleotide excision repair. Signature 4 is also associated with CC>AA dinucleotide substitutions.

Comments:

Signature 29 is found in cancers associated with tobacco chewing and appears different from Signature 4.

Signature 5

Cancer types:

Signature 5 has been found in all cancer types and most cancer samples.

Proposed aetiology:

The aetiology of Signature 5 is unknown.

Additional mutational features:

Signature 5 exhibits transcriptional strand bias for T>C substitutions at ApTpN context.

Comments:

Signature 6

Cancer types:

Signature 6 has been found in 17 cancer types and is most common in colorectal and uterine cancers. In most other cancer types, Signature 6 is found in less than 3% of examined samples.

Proposed aetiology:

Signature 6 is associated with defective DNA mismatch repair and is found in microsatellite unstable tumours.

Additional mutational features:

Signature 6 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 6 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 15, 20, and 26.

Signature 7

Cancer types:

Signature 7 has been found predominantly in skin cancers and in cancers of the lip categorized as head and neck or oral squamous cancers.

Proposed aetiology:

Based on its prevalence in ultraviolet exposed areas and the similarity of the mutational pattern to that observed in experimental systems exposed to ultraviolet light Signature 7 is likely due to ultraviolet light exposure.

Additional mutational features:

Signature 7 is associated with large numbers of CC>TT dinucleotide mutations at dipyrimidines. Additionally, Signature 7 exhibits a strong transcriptional strand-bias indicating that mutations occur at pyrimidines (viz., by formation of pyrimidine-pyrimidine photodimers) and these mutations are being repaired by transcription-coupled nucleotide excision repair.

Comments:

Signature 8

Cancer types:

Signature 8 has been found in breast cancer and medulloblastoma.

Proposed aetiology:

The aetiology of Signature 8 remains unknown.

Additional mutational features:

Signature 8 exhibits weak strand bias for C>A substitutions and is associated with double nucleotide substitutions, notably CC>AA.

Comments:

Signature 9

Cancer types:

Signature 9 has been found in chronic lymphocytic leukaemias and malignant B-cell lymphomas.

Proposed aetiology:

Signature 9 is characterized by a pattern of mutations that has been attributed to polymerase η, which is implicated with the activity of AID during somatic hypermutation.

Additional mutational features:

Comments:

Chronic lymphocytic leukaemias that possess immunoglobulin gene hypermutation (IGHV-mutated) have elevated numbers of mutations attributed to Signature 9 compared to those that do not have immunoglobulin gene hypermutation.

Signature 10

Cancer types:

Signature 10 has been found in six cancer types, notably colorectal and uterine cancer, usually generating huge numbers of mutations in small subsets of samples.

Proposed aetiology:

It has been proposed that the mutational process underlying this signature is altered activity of the error-prone polymerase POLE. The presence of large numbers of Signature 10 mutations is associated with recurrent POLE somatic mutations, viz., Pro286Arg and Val411Leu.

Additional mutational features:

Signature 10 exhibits strand bias for C>A mutations at TpCpT context and T>G mutations at TpTpT context.

Comments:

Signature 10 is associated with some of most mutated cancer samples. Samples exhibiting this mutational signature have been termed ultra-hypermutators.

Signature 11

Cancer types:

Signature 11 has been found in melanoma and glioblastoma.

Proposed aetiology:

Signature 11 exhibits a mutational pattern resembling that of alkylating agents. Patient histories have revealed an association between treatments with the alkylating agent temozolomide and Signature 11 mutations.

Additional mutational features:

Signature 11 exhibits a strong transcriptional strand-bias for C>T substitutions indicating that mutations occur on guanine and that these mutations are effectively repaired by transcription-coupled nucleotide excision repair.

Comments:

Signature 12

Cancer types:

Signature 12 has been found in liver cancer.

Proposed aetiology:

The aetiology of Signature 12 remains unknown.

Additional mutational features:

Signature 12 exhibits a strong transcriptional strand-bias for T>C substitutions.

Comments:

Signature 12 usually contributes a small percentage (<20%) of the mutations observed in a liver cancer sample.

Signature 13

Cancer types:

Signature 13 has been found in 22 cancer types and seems to be commonest in cervical and bladder cancers. In most of these 22 cancer types, Signature 13 is present in at least 10% of samples.

Proposed aetiology:

Signature 13 has been attributed to activity of the AID/APOBEC family of cytidine deaminases converting cytosine to uracil. On the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems, a role for APOBEC1, APOBEC3A and/or APOBEC3B in human cancer appears more likely than for other members of the family. Signature 13 causes predominantly C>G mutations. This may be due to generation of abasic sites after removal of uracil by base excision repair and replication over these abasic sites by REV1.

Additional mutational features:

Transcriptional strand bias of mutations has been observed in exons, but is not present or is weaker in introns.

Comments:

Signature 2 is usually found in the same samples as Signature 13. It has been proposed that activation of AID/APOBEC cytidine deaminases is due to viral infection, retrotransposon jumping or to tissue inflammation. Currently, there is limited evidence to support these hypotheses. A germline deletion polymorphism involving APOBEC3A and APOBEC3B is associated with the presence of large numbers of Signature 2 and 13 mutations and with predisposition to breast cancer. Mutations of similar patterns to Signatures 2 and 13 are commonly found in the phenomenon of local hypermutation present in some cancers, known as kataegis, potentially implicating AID/APOBEC enzymes in this process as well.

Signature 14

Cancer types:

Signature 14 has been observed in four uterine cancers and a single adult low-grade glioma sample.

Proposed aetiology:

The aetiology of Signature 14 remains unknown.

Additional mutational features:

Comments:

Signature 14 generates very high numbers of somatic mutations (>200 mutations per MB) in all samples in which it has been observed.

Signature 15

Cancer types:

Signature 15 has been found in several stomach cancers and a single small cell lung carcinoma.

Proposed aetiology:

Signature 15 is associated with defective DNA mismatch repair.

Additional mutational features:

Signature 15 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 15 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 20, and 26.

Signature 16

Cancer types:

Signature 16 has been found in liver cancer.

Proposed aetiology:

The aetiology of Signature 16 remains unknown.

Additional mutational features:

Signature 16 exhibits an extremely strong transcriptional strand bias for T>C mutations at ApTpN context, with T>C mutations occurring almost exclusively on the transcribed strand.

Comments:

Signature 17

Cancer types:

Signature 17 has been found in oesophagus cancer, breast cancer, liver cancer, lung adenocarcinoma, B-cell lymphoma, stomach cancer and melanoma.

Proposed aetiology:

The aetiology of Signature 17 remains unknown.

Additional mutational features:

Comments:

Signature 1Signature 18

Cancer types:

Signature 18 has been found commonly in neuroblastoma. Additionally, Signature 18 has been also observed in breast and stomach carcinomas.

Proposed aetiology:

The aetiology of Signature 18 remains unknown.

Additional mutational features:

Comments:

Signature 19

Cancer types:

Signature 19 has been found only in pilocytic astrocytoma.

Proposed aetiology:

The aetiology of Signature 19 remains unknown.

Additional mutational features:

Comments:

Signature 20

Cancer types:

Signature 20 has been found in stomach and breast cancers.

Proposed aetiology:

Signature 20 is believed to be associated with defective DNA mismatch repair.

Additional mutational features:

Signature 20 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 20 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 15, and 26.

Signature 21

Cancer types:

Signature 21 has been found only in stomach cancer.

Proposed aetiology:

The aetiology of Signature 21 remains unknown.

Additional mutational features:

Comments:

Signature 21 is found only in four samples all generated by the same sequencing centre. The mutational pattern of Signature 21 is somewhat similar to the one of Signature 26. Additionally, Signature 21 is found only in samples that also have Signatures 15 and 20. As such, Signature 21 is probably also related to microsatellite unstable tumours.

Signature 22

Cancer types:

Signature 22 has been found in urothelial (renal pelvis) carcinoma and liver cancers.

Proposed aetiology:

Signature 22 has been found in cancer samples with known exposures to aristolochic acid. Additionally, the pattern of mutations exhibited by the signature is consistent with the one previous observed in experimental systems exposed to aristolochic acid.

Additional mutational features:

Signature 22 exhibits a very strong transcriptional strand bias for T>A mutations indicating adenine damage that is being repaired by transcription-coupled nucleotide excision repair.

Comments:

Signature 22 has a very high mutational burden in urothelial carcinoma; however, its mutational burden is much lower in liver cancers.

Signature 23

Cancer types:

Signature 23 has been found only in a single liver cancer sample.

Proposed aetiology:

The aetiology of Signature 23 remains unknown.

Additional mutational features:

Signature 23 exhibits very strong transcriptional strand bias for C>T mutations.

Comments:

Signature 24

Cancer types:

Signature 24 has been observed in a subset of liver cancers.

Proposed aetiology:

Signature 24 has been found in cancer samples with known exposures to aflatoxin. Additionally, the pattern of mutations exhibited by the signature is consistent with that previous observed in experimental systems exposed to aflatoxin.

Additional mutational features:

Signature 24 exhibits a very strong transcriptional strand bias for C>A mutations indicating guanine damage that is being repaired by transcription-coupled nucleotide excision repair.

Comments:

Signature 25

Cancer types:

Signature 25 has been observed in Hodgkin lymphomas.

Proposed aetiology:

The aetiology of Signature 25 remains unknown.

Additional mutational features:

Signature 25 exhibits transcriptional strand bias for T>A mutations.

Comments:

This signature has only been identified in Hodgkin’s cell lines. Data is not available from primary Hodgkin lymphomas.

Signature 26

Cancer types:

Signature 26 has been found in breast cancer, cervical cancer, stomach cancer and uterine carcinoma.

Proposed aetiology:

Signature 26 is believed to be associated with defective DNA mismatch repair.

Additional mutational features:

Signature 26 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 26 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 15 and 20.

Signature 27

Cancer types:

Signature 27 has been observed in a subset of kidney clear cell carcinomas.

Proposed aetiology:

The aetiology of Signature 27 remains unknown.

Additional mutational features:

Signature 27 exhibits very strong transcriptional strand bias for T>A mutations. Signature 27 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 28

Cancer types:

Signature 28 has been observed in a subset of stomach cancers.

Proposed aetiology:

The aetiology of Signature 28 remains unknown.

Additional mutational features:

Comments:

Signature 29

Cancer types:

Signature 29 has been observed only in gingivo-buccal oral squamous cell carcinoma.

Proposed aetiology:

Signature 29 has been found in cancer samples from individuals with a tobacco chewing habit.

Additional mutational features:

Signature 29 exhibits transcriptional strand bias for C>A mutations indicating guanine damage that is most likely repaired by transcription-coupled nucleotide excision repair. Signature 29 is also associated with CC>AA dinucleotide substitutions.

Comments:

The Signature 29 pattern of C>A mutations due to tobacco chewing appears different from the pattern of mutations due to tobacco smoking reflected by Signature 4.

Signature 30

Cancer types:

Signature 30 has been observed in a small subset of breast cancers.

Proposed aetiology:

The aetiology of Signature 30 remains unknown.

 


 

Examples in the literature of deposits into or analysis from the COSMIC database

The Genomic Landscapes of Human Breast and Colorectal Cancers from Wood 318 (5853): 11081113 Science 2007

“analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene “mountains” and a much larger number of gene “hills” that are mutated at low frequency. ”

  • found cellular pathways with multiple pathways
  • analyzed a highly curated database (Metacore, GeneGo, Inc.) that includes human protein-protein interactions, signal transduction and metabolic pathways
  • There were 108 pathways that were found to be preferentially mutated in breast tumors. Many of the pathways involved phosphatidylinositol 3-kinase (PI3K) signaling
  • the cancer genome landscape consists of relief features (mutated genes) with heterogeneous heights (determined by CaMP scores). There are a few “mountains” representing individual CAN-genes mutated at high frequency. However, the landscapes contain a much larger number of “hills” representing the CAN-genes that are mutated at relatively low frequency. It is notable that this general genomic landscape (few gene mountains and many gene hills) is a common feature of both breast and colorectal tumors.
  • developed software to analyze multiple mutations and mutation frequencies available from Harvard Bioinformatics at

 

http://bcb.dfci.harvard.edu/~gp/software/CancerMutationAnalysis/cma.htm

 

 

R Software for Cancer Mutation Analysis (download here)

 

CancerMutationAnalysis Version 1.0:

R package to reproduce the statistical analyses of the Sjoblom et al article and the associated Technical Comment. This package is build for reproducibility of the original results and not for flexibility. Future version will be more general and define classes for the data types used. Further details are available in Working Paper 126.

CancerMutationAnalysis Version 2.0:

R package to reproduce the statistical analyses of the Wood et al article. Like its predecessor, this package is still build for reproducibility of the original results and not for flexibility. Further details are available in Working Paper 126

 

 

 

 

 

 

 

 

 

Update 04/27/2019

Review 2018. The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers. Z. Sondka et al. Nature Reviews. 2018.

The Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC) reevaluates the cancer genome landscape periodically and curates the findings into a database of genetic changes occurring in various tumor types.  The 2018 CGC describes in detail the effect of 719 cancer driving genes.  The recent expansion includes functional and mechanistic descriptions of how each gene contributes to disease etiology and in terms of the cancer hallmarks as described by Hanahan and Weinberg.  These functional characteristics show the complexity of the cancer mutational landscape and genome and suggest ” multiple cancer-related functions for many genes, which are often highly tissue-dependent or tumour stage-dependent.”  The 2018 CGC expands a second tier of genes, expanding the list of cancer related genes.

Criteria for curation of genes into CGC (curation process)

  • choosing candidate genes are selected from published literature, conference abstracts, large cancer genome screens deposited in databases, and analysis of current COSMIC database
  • COSMIC data are analyzed to determine presence of patterns of somatic mutations and frequency of such mutations in cancer
  • literature review to determine the role of the gene in cancer
  • Minimum evidence

– at least two publications from different groups shows increased mutation frequency in at least one type of cancer (PubMed)

–  at least two publications from different groups showing experimental evidence of functional involvement in at least one hallmark of cancer in order to classify the mutant gene as oncogene, tumor suppressor, or fusion partner (like BCR-Abl)

  • independent assessment by at least two postdoctoral fellows
  • gene must be classified as either Tier 1 of Tier 2 CGC gene
  • inclusion in database
  • continued curation efforts

definitions:

Tier 1 gene: genes which have strong evidence from both mutational and functional analysis as being involved in cancer

Tier 2 gene: genes with mutational patterns typical of cancer drivers but not functionally characterized as well as genes with published mechanistic description of involvement in cancer but without proof of somatic mutations in cancer

Current Status of Tier 1 and Tier 2 genes in CGC

Tier 1 genes (574 genes): include 79 oncogenes, 140 tumor suppressor genes, 93 fusion partners

Tier 2 genes (719 genes): include 103 oncogenes, 181 tumor suppressors, 134 fusion partners and 31 with unknown function

 

 

 

 

 

 

 

 

 

 

 

Advertisements

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

 

Nature Genetics (2013) doi:10.1038/ng.2705

Independent specialization of the human and mouse X chromosomes for the male germ line

  1. Whitehead Institute, Cambridge, Massachusetts, USA.

    • Jacob L Mueller,
    • Helen Skaletsky,
    • Laura G Brown,
    • Sara Zaghlul &
    • David C Page
  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Helen Skaletsky,
    • Laura G Brown &
    • David C Page
  3. The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Susan Rock,
    • Tina Graves,
    • Wesley C Warren &
    • Richard K Wilson
  4. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Katherine Auger
  5. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • David C Page

Contributions

J.L.M., H.S., W.C.W., R.K.W. and D.C.P. planned the project. J.L.M. and L.G.B. performed BAC mapping. J.L.M. performed RNA deep sequencing. T.G., S.R., K.A. and S.Z. were responsible for finished BAC sequencing. J.L.M. and H.S. performed sequence analyses. J.L.M. and D.C.P. wrote the manuscript.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Nature Genetics (2013) doi:10.1038/ng.2705

Received

 11 February 2013 Accepted

20 June 2013 Published online

21 July 2013

We compared the human and mouse X chromosomes to systematically test Ohno’s law, which states that the gene content of X chromosomes is conserved across placental mammals1. First, we improved the accuracy of the human X-chromosome reference sequence through single-haplotype sequencing of ampliconic regions. The new sequence closed gaps in the reference sequence, corrected previously misassembled regions and identified new palindromic amplicons. Our subsequent analysis led us to conclude that the evolution of human and mouse X chromosomes was bimodal. In accord with Ohno’s law, 94–95% of X-linked single-copy genes are shared by humans and mice; most are expressed in both sexes. Notably, most X-ampliconic genes are exceptions to Ohno’s law: only 31% of human and 22% of mouse X-ampliconic genes had orthologs in the other species. X-ampliconic genes are expressed predominantly in testicular germ cells, and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.

Refined X Chromosome Assembly Hints at Possible Role in Sperm Production

July 22, 2013

NEW YORK (GenomeWeb News) – A US and UK team that delved into previously untapped stretches of sequence on the mammalian X chromosome has uncovered clues that sequences on the female sex chromosome may play a previously unappreciated role in sperm production.

The work, published online yesterday in Nature Genetics, also indicated such portions of the X chromosome may be prone to genetic changes that are more rapid than those described over other, better-characterized X chromosome sequences.

“We view this as the double life of the X chromosome,” senior author David Page, director of the Whitehead Institute, said in a statement.

“[T]he story of the X has been the story of X-linked recessive diseases, such as color blindness, hemophilia, and Duchenne’s muscular dystrophy,” he said. “But there’s another side to the X, a side that is rapidly evolving and seems to be attuned to the reproductive needs of males.”

As part of a mouse and human X chromosome comparison intended to assess the sex chromosome’s similarities across placental mammals, Page and his colleagues used a technique called single-haplotype iterative mapping and sequencing, or SHIMS, to scrutinize human X chromosome sequence and structure in more detail than was available previously.

With the refined human X chromosome assembly and existing mouse data, the team did see cross-mammal conservation for many X-linked genes, particularly those present in single copies. But that was not the case for a few hundred species-specific genes, many of which fell in segmentally duplicated, or “ampliconic,” parts of the X chromosome. Moreover, those genes were prone to expression by germ cells in male testes tissue, pointing to a potential role in sperm production-related processes.

“X-ampliconic genes are expressed predominantly in testicular germ cells,” the study authors noted, “and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.”

The work was part of a larger effort to look at a theory known as Ohno’s law, which predicts extensive X-linked gene similarities from one placental mammal to the next, Page and company turned to the same SHIMS method they used to get a more comprehensive view of the Y chromosome for previous studies.

Using that sequencing method, the group resequenced portions of the human X chromosome, originally assembled from a mishmash of sequence from the 16 or more individuals whose DNA was used to sequence the human X chromosome reference.

Their goal: to track down sections of segmental duplication, called ampliconic regions, that may have been missed or assembled incorrectly in the mosaic human X chromosome sequence.

“Ampliconic regions assembled from multiple haplotypes may have expansions, contractions, or inversions that do not accurately reflect the structure of any extant haplotype,” the study’s authors explained.

“To thoroughly test Ohno’s law,” they wrote, “we constructed a more accurate assembly of the human X chromosome’s ampliconic regions to compare the gene contents of the human and mouse X chromosomes.”

The team focused their attention on 29 predicted ampliconic regions of the human X chromosome, using SHIMS to generate millions of bases of non-overlapping X chromosome sequence.

With that sequence in hand, they went on to refine the human X chromosome assembly before comparing it with the reference sequence for the mouse X chromosome, which already represented just one mouse haplotype.

The analysis indicated that 144 of the genes on the human X chromosome don’t have orthologs in mice, while 197 X-linked mouse genes lack human orthologs.

A minority of those species-specific genes arose as the result of gene duplication or gene loss events since the human and mouse lineages split from one around 80 million years ago, researchers determined. But most appear to have resulted from retrotransposition or transposition events involving sequences from autosomal chromosomes.

And when the team used RNA sequencing and existing gene expression data to look at which mouse and human tissues flip on particular genes, it found that many of the species-specific genes on the X chromosome showed preferential expression in testicular cells known for their role in sperm production.

Based on such findings, the study’s authors concluded that “the gene repertoires of the human and mouse X chromosomes are products of two complementary evolutionary processes: conservation of single-copy genes that serve in functions shared by the sexes and ongoing gene acquisition, usually involving the formation of amplicons, which leads to the differentiation and specialization of X chromosomes for functions in male gametogenesis.”

The group plans to incorporate results of its SHIMS-based assembly into the X chromosome portion of the human reference genome.

“This is a collection of genes that has largely eluded medical geneticists,” the study’s first author Jacob Mueller, a post-doctoral researcher in Page’s Whitehead lab, said in a statement. “Now that we’re confident of the assembly and gene content of these highly repetitive regions on the X chromosome, we can start to dissect their biological significance.”

Related Stories

SOURCE

http://www.genomeweb.com//node/1256251?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=X%20Chromosome’s%20Possible%20New%20Role;%20NanoString%20Coverage%20Initiated;%20SynapDx%20Raises%20Funds;%20More%20-%2007/22/2013%2010:50:00%20AM

 

REFERENCES in the Nature Genetics

  • Ohno, S. Sex Chromosomes and Sex-Linked Genes (Springer, Berlin, 1967).
  1. Kuroiwa, A. et al. Conservation of the rat X chromosome gene order in rodent species.Chromosome Res. 9, 61–67 (2001).
  2. Delgado, C.L., Waters, P.D., Gilbert, C., Robinson, T.J. & Graves, J.A. Physical mapping of the elephant X chromosome: conservation of gene order over 105 million years.Chromosome Res. 17, 917–926 (2009).
  3. Prakash, B., Kuosku, V., Olsaker, I., Gustavsson, I. & Chowdhary, B.P. Comparative FISH mapping of bovine cosmids to reindeer chromosomes demonstrates conservation of the X-chromosome. Chromosome Res. 4, 214–217 (1996).
  4. Ross, M.T. et al. The DNA sequence of the human X chromosome. Nature 434, 325–337(2005).
  5. Veyrunes, F. et al. Bird-like sex chromosomes of platypus imply recent origin of mammal sex chromosomes. Genome Res. 18, 965–973 (2008).
  6. Watanabe, T.K. et al. A radiation hybrid map of the rat genome containing 5,255 markers.Nat. Genet. 22, 27–36 (1999).
  7. Raudsepp, T. et al. Exceptional conservation of horse-human gene order on X chromosome revealed by high-resolution radiation hybrid mapping. Proc. Natl. Acad. Sci. USA 101,2386–2391 (2004).
  8. Band, M.R. et al. An ordered comparative map of the cattle and human genomes. Genome Res. 10, 1359–1368 (2000).
  9. Murphy, W.J., Sun, S., Chen, Z.Q., Pecon-Slattery, J. & O’Brien, S.J. Extensive conservation of sex chromosome organization between cat and human revealed by parallel radiation hybrid mapping. Genome Res. 9, 1223–1230 (1999).
  10. Spriggs, H.F. et al. Construction and integration of radiation-hybrid and cytogenetic maps of dog chromosome X. Mamm. Genome 14, 214–221 (2003).
  11. Palmer, S., Perry, J. & Ashworth, A. A contravention of Ohno’s law in mice. Nat. Genet. 10,472–476 (1995).
  12. Rugarli, E.I. et al. Different chromosomal localization of the Clcn4 gene in Mus spretus and C57BL/6J mice. Nat. Genet. 10, 466–471 (1995).
  13. She, X. et al. Shotgun sequence assembly and recent segmental duplications within the human genome. Nature 431, 927–930 (2004).
  14. Olivier, M. et al. A high-resolution radiation hybrid map of the human genome draft sequence. Science 291, 1298–1302 (2001).
  15. Dietrich, W.F. et al. A comprehensive genetic map of the mouse genome. Nature 380,149–152 (1996).
  16. Church, D.M. et al. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 7, e1000112 (2009).
  17. Tishkoff, S.A. & Kidd, K.K. Implications of biogeography of human populations for ‘race’ and medicine. Nat. Genet. 36, S21–S27 (2004).
  18. Bovee, D. et al. Closing gaps in the human genome with fosmid resources generated from multiple individuals. Nat. Genet. 40, 96–101 (2008).
  19. Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes.Nature 453, 56–64 (2008).
  20. Skaletsky, H. et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423, 825–837 (2003).
  21. Hughes, J.F. et al. Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content. Nature 463, 536–539 (2010).
  22. Kuroda-Kawaguchi, T. et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat. Genet. 29, 279–286(2001).
  23. Bellott, D.W. et al. Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition. Nature 466, 612–616 (2010).
  24. Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).
  25. Wade, C.M. et al. Genome sequence, comparative analysis, and population genetics of the domestic horse. Science 326, 865–867 (2009).
  26. International Chicken Genome Sequencing Consortium. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432,695–716 (2004).
  27. Wang, E.T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456,470–476 (2008).
  28. Mortazavi, A., Williams, B.A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621–628 (2008).
  29. Bradley, R.K., Merkin, J., Lambert, N.J. & Burge, C.B. Alternative splicing of RNA triplets is often regulated and accelerates proteome evolution. PLoS Biol. 10, e1001229 (2012).
  30. Handel, M.A. & Eppig, J.J. Sertoli cell differentiation in the testes of mice genetically deficient in germ cells. Biol. Reprod. 20, 1031–1038 (1979).
  31. Mueller, J.L. et al. The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression. Nat. Genet. 40, 794–799 (2008).
  32. Coyne, J.A. & Orr, H.A. Speciation (Sinauer Associates, Sunderland, MA, 2004).
  33. Elliott, R.W. et al. Genetic analysis of testis weight and fertility in an interspecies hybrid congenic strain for chromosome X. Mamm. Genome 12, 45–51 (2001).
  34. Elliott, R.W., Poslinski, D., Tabaczynski, D., Hohman, C. & Pazik, J. Loci affecting male fertility in hybrids between Mus macedonicus and C57BL/6. Mamm. Genome 15, 704–710(2004).
  35. Storchová, R. et al. Genetic analysis of X-linked hybrid sterility in the house mouse. Mamm. Genome 15, 515–524 (2004).
  36. Fujita, P.A. et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res.39, D876–D882 (2011).
  37. Schwartz, S. et al. Human-mouse alignments with BLASTZ. Genome Res. 13, 103–107(2003).
  38. Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297,1003–1007 (2002).
  39. Osoegawa, K. et al. A bacterial artificial chromosome library for sequencing the complete human genome. Genome Res. 11, 483–496 (2001).
  40. Salido, E.C. et al. Cloning and expression of the mouse pseudoautosomal steroid sulphatase gene (Sts). Nat. Genet. 13, 83–86 (1996).
  41. Yeh, R.F., Lim, L.P. & Burge, C.B. Computational inference of homologous gene structures in the human genome. Genome Res. 11, 803–816 (2001).
  42. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).
  43. Thornton, K. & Long, M. Rapid divergence of gene duplicates on the Drosophila melanogaster X chromosome. Mol. Biol. Evol. 19, 918–925 (2002).
  44. Trapnell, C., Pachter, L. & Salzberg, S.L. TopHat: discovering splice junctions with RNA-Seq.Bioinformatics 25, 1105–1111 (2009).
  45. Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511–515(2010).
  46. Brawand, D. et al. The evolution of gene expression levels in mammalian organs. Nature478, 343–348 (2011).
  47. Deng, X. et al. Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nat. Genet. 43,1179–1185 (2011).

 

Read Full Post »


Curator: Ritu Saxena, Ph.D.

Introduction and Research Relevance:

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%–5%. The cancer’s lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis.

http://www.ncbi.nlm.nih.gov/pubmed/16702400

Also, it has been well documented that despite much progress in its molecular characterization, Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy.

Recent article published in the journal Nature talks about discovering the link between a gene and the prognosis of Pancreatic Ductal Adenocarcenoma (PDA). The discovery might have therapeutic relevance in PDA.

Although previous work had attributed a pro-survival role to USP9X in human neoplasia, the researchers found instead that loss of Usp9x protects pancreatic cancer cells from death. Thus, the study proposed USP9X to be a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature11114.pdf

News brief: (http://www.sanger.ac.uk/about/press/2012/120429.html)

29 April 2012

Gene against pancreatic cancer discovered

Study points to potential new treatment for deadly pancreatic cancer

In a study published in Nature (Sunday 29 April), researchers have identified a potential new therapeutic target for pancreatic cancer.

The team found that when a gene involved in protein degradation is switched-off through chemical tags on the DNA’s surface, pancreatic cancer cells are protected from the bodies’ natural cell death processes, become more aggressive, and can rapidly spread.

Pancreatic cancer kills around 8,000 people every year in the UK and, although survival rates are gradually improving, fewer than 1 in 5 patients survive for a year or more following their diagnosis.

Co-lead author Professor David Tuveson, from Cancer Research UK’s Cambridge Research Institute, said: “The genetics of pancreatic cancer has already been studied in some detail, so we were surprised to find that this gene hadn’t been picked up before. We suspected that the fault wasn’t in the genetic code at all, but in the chemical tags on the surface of the DNA that switch genes on and off, and by running more lab tests we were able to confirm this.”

The team expects this gene, USP9X, could be faulty in up to 15 per cent of pancreatic cancers, raising the prospect that existing drugs, which strip away these chemical tags, could be an effective way of treating some pancreatic cancers.

” This study strengthens our emerging understanding that we must also look into the biology of cells to identify all the genes that play a role in cancer. ” Dr David Adams

“Drugs which strip away these tags are already showing promise in lung cancer and this study suggests they could also be effective in treating up to 15 per cent of pancreatic cancers,” continues Professor Tuveson.

The researchers used a mouse model of pancreatic cancer to screen for genes that speed up pancreatic cancer growth using a technique called ‘Sleeping Beauty transposon mutagenesis’. This system uses mobile genetic elements that hop around the cell’s DNA from one location to the next. Cells that acquire mutations in genes that contribute to cancer development will grow out and ‘driver’ cancer genes may be identified.

By introducing the Sleeping Beauty transposon into mice pre-disposed to develop pancreatic cancer, the researchers were able to screen for a class of genes called a tumour suppressor that, under normal circumstances, would protect against cancer. These genes are a bit like the cell’s ‘brakes’, so when they become faulty there is little to stop the cell from multiplying out of control.

This approach uncovered many genes already linked to pancreatic cancer. But unexpectedly, USP9X, was identified.

Co-lead author Dr David Adams, from the Wellcome Trust Sanger Institute, said: “The human genome sequence has delivered many promising new leads and transformed our understanding of cancer. Without it, we would have only a small, shattered glimpse into the causes of this disease. This study strengthens our emerging understanding that we must also look into the biology of cells to identify all the genes that play a role in cancer.”

http://www.sanger.ac.uk/about/press/2012/120429.html

Read Full Post »