Transposable elements that have recently been mobile in the human genome

Abstract Background Transposable elements (TE) comprise nearly half of the human genome and their insertions have profound effects to human genetic diversification and as well as disease. Despite their abovementioned significance, there is no consensus on the TE subfamilies that remain active in the human genome. In this study, we therefore developed a novel statistical test for recently mobile subfamilies (RMSs), based on patterns of overlap with > 100,000 polymorphic indels. Results Our analysis produced a catalogue of 20 high-confidence RMSs, which excludes many false positives in public databases. Intriguingly though, it includes HERV-K, an LTR subfamily previously thought to be extinct. The RMS catalogue is strongly enriched for contributions to germline genetic disorders (P = 1.1e-10), and thus constitutes a valuable resource for diagnosing disorders of unknown aetiology using targeted TE-insertion screens. Remarkably, RMSs are also highly enriched for somatic insertions in diverse cancers (P = 2.8e-17), thus indicating strong correlations between germline and somatic TE mobility. Using CRISPR/Cas9 deletion, we show that an RMS-derived polymorphic TE insertion increased the expression of RPL17, a gene associated with lower survival in liver cancer. More broadly, polymorphic TE insertions from RMSs were enriched near genes with allele-specific expression, suggesting widespread effects on gene regulation. Conclusions By using a novel statistical test we have defined a catalogue of 20 recently mobile transposable element subfamilies. We illustrate the gene regulatory potential of RMS-derived polymorphic TE insertions, using CRISPR/Cas9 deletion in vitro on a specific candidate, as well as by genome wide analysis of allele-specific expression. Our study presents novel insights into TE mobility and regulatory potential and provides a key resource for human disease genetics and population history studies.

Download Full-text

An in vitro ES cell imprinting model shows that imprinted expression of the Igf2r gene arises from an allele-specific expression bias

Development ◽

10.1242/dev.032060 ◽

2009 ◽

Vol 136 (3) ◽

pp. 437-448 ◽

Cited By ~ 43

Author(s):

P. A. Latos ◽

S. H. Stricker ◽

L. Steenpass ◽

F. M. Pauler ◽

R. Huang ◽

...

Keyword(s):

Es Cell ◽

Specific Expression ◽

Allele Specific Expression ◽

Expression Bias ◽

Allele Specific

Download Full-text

Allele-specific expression reveals interactions between genetic variation and environment

10.1101/025874 ◽

2015 ◽

Cited By ~ 4

Author(s):

David A Knowles ◽

Joe R Davis ◽

Anil Raj ◽

Xiaowei Zhu ◽

James B Potash ◽

...

Keyword(s):

Rna Sequencing ◽

Cellular Level ◽

Specific Expression ◽

Allele Specific Expression ◽

Sequencing Studies ◽

Allele Specific ◽

Gxe Interactions ◽

Over Dispersion ◽

The Impact

The impact of environment on human health is dramatic, with major risk factors including substance use, diet and exercise. However, identifying interactions between the environment and an individual's genetic background (GxE) has been hampered by statistical and computational challenges. By combining RNA sequencing of whole blood and extensive environmental annotations collected from 922 individuals, we have evaluated GxE interactions at a cellular level. We have developed EAGLE, a hierarchical Bayesian model for identifying GxE interactions based on association between environment and allele-specific expression (ASE). EAGLE increases power by leveraging the controlled, within-sample comparison of environmental impact on different genetic backgrounds provided by ASE, while also taking into account technical covariates and over-dispersion of sequencing read counts. EAGLE identifies 35 GxE interactions, a substantial increase over standard GxE testing. Among EAGLE hits are variants that modulate response to smoking, exercise and blood pressure medication. Further, application of EAGLE identifies GxE interactions to infection response that replicate results reported in vitro, demonstrating the power of EAGLE to accurately identify GxE candidates from large RNA sequencing studies.

Download Full-text

239 ALLELE-SPECIFIC EXPRESSION OF X CHROMOSOME-LINKED GENE MAO-A DURING PRE-IMPLANTATION DEVELOPMENT IN BOVINE EMBRYO

Reproduction Fertility and Development ◽

10.1071/rdv22n1ab239 ◽

2010 ◽

Vol 22 (1) ◽

pp. 277

Author(s):

A. R. Ferreira ◽

G. M. Machado ◽

T. O. Diesel ◽

J. O. Carvalho ◽

R. Rumpf ◽

...

Keyword(s):

X Chromosome ◽

Bos Taurus ◽

Paternal Allele ◽

Specific Expression ◽

Allele Specific Expression ◽

X Chromosomes ◽

Linked Gene ◽

Mao A ◽

Allele Specific

The in vitro embryo culture might affect epigenetic mechanisms, which are involved in controlling the expression of genes related to embryonic development and inactivation of X chromosome. Female mammals have 2 X chromosomes, and males have only 1. This has led to a particular mechanism of evolution of dosage compensation, called X-chromosome inactivation, an important epigenetic event that must occur in all mammalian female embryos. During embryogenesis, at the late blastocyst development (Xue F et al. 2002 Nature Genet. 31, 216220), 1 of the 2 X chromosomes is randomly inactivated in each cell of the inner cell mass and preferentially X paternal in trophoblast. The aim of this study was to characterize the allele-specific expression of the X chromosome-linked gene monoamine oxidase type A (MAO-A) during in vitro pre-implantation embryo development in bovine. For phenotyping of the MAO-A gene, the RT-PCR restriction fragment length polymorphism technique was used. Primers were designed flanking a single nucleotide polymorphism and the sequence of forward inner primer creating a site of restriction to the RsaI enzyme, thus allowing the detection of allele-specific expression (Bos taurus Taurus × Bos taurus indicus). Oocytes were aspirated from 9 Nelore heifers homozygous for theA allele previously genotyped. The oocytes were selected, matured in vitro, and inseminated with X-sorted sperm from a Holstein bull homozygous for the G allele. Two pools of 10 heterozygous in vitro embryos of each developmental stage, 4-cell [44 h post-insemination (p.i.)], 8- to 16-cell (72 h p.i.), morula (144 h p.i.), blastocyst (156 p.i.), and expanded blastocyst (168 h p.i.), were produced and frozen until RNA extraction. Total RNA was extracted using Invisorb® Spin Cell RNA Mini Kit (Invitek, Berlin, Germany) according to the manufacturer’s protocol, and residual genomic DNA was removed with DNase I treatment. cDNA was done using Oligo dT primers (Invitrogen) and superscript III reverse transcriptase (Invitrogen). Nested PCR for each pool was performed and then the amplicons were digested with 10 U of RsaI enzyme (Promega, Madison, WI, USA). The products were separated by electrophoresis on a 3% agarose gel stained with ethidium bromide. The results showed that both alleles were expressionally represented in the 4-cell, 8- to 16-cell, and expanded blastocyst stages, with the X paternal allele disappearing in morula and blastocyst. We can conclude that both, maternal and paternal X chromosomes, are activated in the 2 earliest stages, inactivated in the morula and blastocyst stages, and reactivated in the expanded blastocyst stage. This research was supported by Embrapa Genetic Resources and Biotechnology and the Brazilian National Council for Scientific and Technological Development (CNPq).

Download Full-text

Allele-specific expression of the serotonin transporter and its transcription factors following lamotrigine treatment in vitro

American Journal of Medical Genetics Part B Neuropsychiatric Genetics ◽

10.1002/ajmg.b.32178 ◽

2013 ◽

Vol 162 (5) ◽

pp. 474-483 ◽

Cited By ~ 4

Author(s):

Ursula M. D'Souza ◽

Georgia Powell-Smith ◽

Kate Haddley ◽

Timothy R. Powell ◽

Vivien J. Bubb ◽

...

Keyword(s):

Transcription Factors ◽

Serotonin Transporter ◽

Specific Expression ◽

Allele Specific Expression ◽

Allele Specific

Download Full-text

Allele-specific expression of the MAOA gene and X chromosome inactivation in in vitro produced bovine embryos

Molecular Reproduction and Development ◽

10.1002/mrd.21192 ◽

2010 ◽

Vol 77 (7) ◽

pp. 615-621 ◽

Cited By ~ 10

Author(s):

A.R. Ferreira ◽

G.M. Machado ◽

T.O. Diesel ◽

J.O. Carvalho ◽

R. Rumpf ◽

...

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Bovine Embryos ◽

Specific Expression ◽

Allele Specific Expression ◽

Maoa Gene ◽

Allele Specific

Download Full-text

Investigation of allele specific expression in various tissues of broiler chickens using the detection tool VADT

Scientific Reports ◽

10.1038/s41598-021-83459-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

M. Joseph Tomlinson ◽

Shawn W. Polson ◽

Jing Qiu ◽

Juniper A. Lake ◽

William Lee ◽

...

Keyword(s):

Broiler Chickens ◽

Nucleotide Polymorphisms ◽

Rna Seq ◽

Specific Expression ◽

Single Nucleotide ◽

Allele Specific Expression ◽

Detection Tool ◽

Commercial Broiler ◽

Significant Phenomenon ◽

Allele Specific

AbstractDifferential abundance of allelic transcripts in a diploid organism, commonly referred to as allele specific expression (ASE), is a biologically significant phenomenon and can be examined using single nucleotide polymorphisms (SNPs) from RNA-seq. Quantifying ASE aids in our ability to identify and understand cis-regulatory mechanisms that influence gene expression, and thereby assist in identifying causal mutations. This study examines ASE in breast muscle, abdominal fat, and liver of commercial broiler chickens using variants called from a large sub-set of the samples (n = 68). ASE analysis was performed using a custom software called VCF ASE Detection Tool (VADT), which detects ASE of biallelic SNPs using a binomial test. On average ~ 174,000 SNPs in each tissue passed our filtering criteria and were considered informative, of which ~ 24,000 (~ 14%) showed ASE. Of all ASE SNPs, only 3.7% exhibited ASE in all three tissues, with ~ 83% showing ASE specific to a single tissue. When ASE genes (genes containing ASE SNPs) were compared between tissues, the overlap among all three tissues increased to 20.1%. Our results indicate that ASE genes show tissue-specific enrichment patterns, but all three tissues showed enrichment for pathways involved in translation.

Download Full-text