HCONDELs

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hCONDELs refer to regions of deletions within the human genome containing sequences that are highly conserved among closely related relatives. Almost all of these deletions fall within regions that perform non-coding functions. These represent a new class of regulatory sequences and may have played an important role in the development of specific traits and behavior that distinguish closely related organisms from each other. [1] [2]

Contents

Nomenclature

The group of CONDELs of a specific organism is specified by prefixing the CONDELs with the first letter of the organism. For instance, hCONDELs refer to the group of CONDELs found in humans whereas mCONDELs and cCONDELs refer to mouse and chimpanzee CONDELs respectively.

Identification of CONDELs

The term hCONDEL was first used in the 2011 Nature article by McLean et al. [3] in whole-genome comparison analysis. [4] This involved firstly identifying a subset of 37,251 human deletions (hDELs) [5] through pairwise comparisons of chimpanzee and macaque genomes. [6] Chimpanzee sequences highly conserved in other species were then identified by pairwise alignment of chimpanzee with macaque, mouse and chicken sequences with BLASTZ [7] followed by multiple alignment of the pairwise alignments done with MULTIZ. [8] The highly conserved chimpanzee sequences were searched against the human genome using BLAT to identify conserved regions not present in humans. This identified 583 regions of deletions that were then referred to as hCONDELs. 510 of these identified hCONDELs were then validated computationally with 39 of these being validated by polymerase chain reaction (PCR).

Characteristics

hCONDELs in humans cover approximately 0.14% of chimpanzee genome. The number of hCONDELs currently identified is 583 using the genome-wide comparison method; however, validation of these predicated regions of deletions through polymerase chain reaction methods produces 510 hCONDELs. The remainder of these hCONDELs are either false-positives or non-existent genes. hCONDELs have been confirmed through PCR with 88 percent of these shown to have been lost from the draft Neanderthal genome. [9] hCONDELs, on average, remove about 95 base pairs (bp) of highly conserved sequences from the human genome. The median size of these 510 validated CONDELs is about 2,804 bp, thus showing a diverse range in length of the characteristic deletions. Another noticeable characteristic of hCONDELs (and other groups of identified CONDELs such as those from mouse and chimpanzee) is that they tend to be specifically skewed towards GC poor regions. [10] Simulations show that hCONDELs are enriched near genes [11] involved in hormone receptor signaling and neural function, and near genes encoding fibronectin-type-III-or CD80-like immunoglobulin C2-set domains.

Impact in humans

Sialic acid loss

Of the 510 identified hCONDELs, only one of these deletions has been shown to remove a 92 bp sequence that is part of a protein-coding region in the human sequence. The deletion that affects the protein coding region [12] in humans results in a frameshift mutation in the CMAH gene which codes for the cytidine monophosphate-N-acetylneurminic acid hydroxylase-like protein, an enzyme involved in the production of N-glycolylneuraminic acid, one type of sialic acid. Sialic acid is known to play a crucial part in cell signaling pathways and interaction processes. The loss of this gene is evident in the undetectable levels of sialic acid in humans but highly present in mouse, pig, chimpanzee and other mammal tissues and may provide more insight into the historic background of human evolution. [13]

The mechanisms and time of occurrence of hCONDELs are not entirely understood but given that conserved non-coding sequences play a major developmental role through regulation of genes, [1] their loss in regions of deletions, it is expected that their loss in hCONDELs will result in developmental consequences that can be observed in human-specific traits. In situ hybridization experiments done by Mclean et al. [3] by fusion of mouse constructs fused to basal promoter with LacZ expression [14] for hCONDELs near the androgen receptor (AR) locus and the growth arrest and DNA-damage-inducible protein GADD45 gamma (GADD45G) locus suggest a role in deletions that affect regulatory sequences in humans.

Loss of whiskers and penile spine

An hCONDEL located near the locus of the androgen receptor (AR) gene may be responsible for the loss of whiskers and penile spines in humans compared to its close relatives, including chimpanzees.[ citation needed ] The 60.7kb hCONDEL which is located near the AR locus has been found to be responsible for removing a 5 kb sequence that codes for an enhancer [15] for the AR locus. Using the mouse construct with LacZ expression showed localization of this hCONDEL region (AR enhancer) to the mesenchyme of vibrissae follicles and the mesoderm cells of penile organs.

Expansion of brain size

Many hCONDELs are located around genes expressed during cortical neurogenesis. A 3,181 bp hCONDEL which is located near the GADD45G gene removes a forebrain-specific p300 enhancer binding site. The removal of this region, known to function as a suppressor, specifically increases the proliferation of the subventricular zone (SVZ) of the septum. The loss of this SVZ enhancer region in an hCONDEL may provide further insights into the role of DNA sequence changes that may have resulted in evolution of the human brain [16] and may provide a better understanding of the evolution of humans.

Related Research Articles

<span class="mw-page-title-main">Human genome</span> Complete set of nucleic acid sequences for humans

The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the nuclear genome and the mitochondrial genome. Human genomes include both protein-coding DNA sequences and various types of DNA that does not encode proteins. The latter is a diverse category that includes DNA coding for non-translated RNA, such as that for ribosomal RNA, transfer RNA, ribozymes, small nuclear RNAs, and several types of regulatory RNAs. It also includes promoters and their associated gene-regulatory elements, DNA playing structural and replicatory roles, such as scaffolding regions, telomeres, centromeres, and origins of replication, plus large numbers of transposable elements, inserted viral DNA, non-functional pseudogenes and simple, highly repetitive sequences. Introns make up a large percentage of non-coding DNA. Some of this non-coding DNA is non-functional junk DNA, such as pseudogenes, but there is no firm consensus on the total amount of junk DNA.

<span class="mw-page-title-main">Genome project</span>

Genome projects are scientific endeavours that ultimately aim to determine the complete genome sequence of an organism and to annotate protein-coding genes and other important genome-encoded features. The genome sequence of an organism includes the collective DNA sequences of each chromosome in the organism. For a bacterium containing a single chromosome, a genome project will aim to map the sequence of that chromosome. For the human species, whose genome includes 22 pairs of autosomes and 2 sex chromosomes, a complete genome sequence will involve 46 separate chromosome sequences.

An Alu element is a short stretch of DNA originally characterized by the action of the Arthrobacter luteus (Alu) restriction endonuclease. Alu elements are the most abundant transposable elements, containing over one million copies dispersed throughout the human genome. Alu elements were thought to be selfish or parasitic DNA, because their sole known function is self reproduction. However, they are likely to play a role in evolution and have been used as genetic markers. They are derived from the small cytoplasmic 7SL RNA, a component of the signal recognition particle. Alu elements are highly conserved within primate genomes and originated in the genome of an ancestor of Supraprimates.

<span class="mw-page-title-main">Comparative genomics</span>

Comparative genomics is a field of biological research in which the genomic features of different organisms are compared. The genomic features may include the DNA sequence, genes, gene order, regulatory sequences, and other genomic structural landmarks. In this branch of genomics, whole or large parts of genomes resulting from genome projects are compared to study basic biological similarities and differences as well as evolutionary relationships between organisms. The major principle of comparative genomics is that common features of two organisms will often be encoded within the DNA that is evolutionarily conserved between them. Therefore, comparative genomic approaches start with making some form of alignment of genome sequences and looking for orthologous sequences in the aligned genomes and checking to what extent those sequences are conserved. Based on these, genome and molecular evolution are inferred and this may in turn be put in the context of, for example, phenotypic evolution or population genetics.

Indel (insertion-deletion) is a molecular biology term for an insertion or deletion of bases in the genome of an organism. Indels ≥ 50 bases in length are classified as structural variants.

<span class="mw-page-title-main">Conserved sequence</span> Similar DNA, RNA or protein sequences within genomes or among species

In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids or proteins across species, or within a genome, or between donor and receptor taxa. Conservation indicates that a sequence has been maintained by natural selection.

<span class="mw-page-title-main">Chimpanzee genome project</span> Effort to determine the DNA sequence of the chimpanzee genome

The Chimpanzee Genome Project was an effort to determine the DNA sequence of the chimpanzee genome. Sequencing began in 2005 and by 2013 twenty-four individual chimpanzees had been sequenced. This project was folded into the Great Ape Genome Project.

Human evolutionary genetics studies how one human genome differs from another human genome, the evolutionary past that gave rise to the human genome, and its current effects. Differences between genomes have anthropological, medical, historical and forensic implications and applications. Genetic data can provide important insights into human evolution.

<span class="mw-page-title-main">CTCF</span> Transcription factor

Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.

<span class="mw-page-title-main">Small nucleolar RNA SNORD115</span>

In molecular biology, SNORD115 is a non-coding RNA (ncRNA) molecule known as a small nucleolar RNA which usually functions in guiding the modification of other non-coding RNAs. This type of modifying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis. HBII-52 refers to the human gene, whereas RBII-52 is used for the rat gene and MBII-52 is used for naming the mouse gene.

<span class="mw-page-title-main">GPR85</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 85 is a protein that in humans is encoded by the GPR85 gene.

<span class="mw-page-title-main">Sodium-coupled neutral amino acid transporter 3</span> Protein-coding gene in the species Homo sapiens

Sodium-coupled neutral amino acid transporter 3 is a protein that in humans is encoded by the SLC38A3 gene.

<span class="mw-page-title-main">ARID2</span> Protein-coding gene in humans

AT-rich interactive domain-containing protein 2 (ARID2) is a protein that in humans is encoded by the ARID2 gene.

<span class="mw-page-title-main">DGLUCY</span> Protein-coding gene in the species Homo sapiens

DGLUCY is a protein that in humans is encoded by the DGLUCY gene.

<span class="mw-page-title-main">ITFG3</span> Protein-coding gene in the species Homo sapiens

Protein ITFG3 also known as family with sequence similarity 234 member A (FAM234A) is a protein that in humans is encoded by the ITFG3 gene. Here, the gene is explored as encoded by mRNA found in Homo sapiens. The FAM234A gene is conserved in mice, rats, chickens, zebrafish, dogs, cows, frogs, chimpanzees, and rhesus monkeys. Orthologs of the gene can be found in at least 220 organisms including the tropical clawed frog, pandas, and Chinese hamsters. The gene is located at 16p13.3 and has a total of 19 exons. The mRNA has a total of 3224 bp and the protein has 552 aa. The molecular mass of the protein produced by this gene is 59660 Da. It is expressed in at least 27 tissue types in humans, with the greatest presence in the duodenum, fat, small intestine, and heart.

<span class="mw-page-title-main">Long non-coding RNA</span> Non-protein coding transcripts longer than 200 nucleotides

Long non-coding RNAs are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Given that some lncRNAs have been reported to have the potential to encode small proteins or micro-peptides, the latest definition of lncRNA is a class of RNA molecules of over 200 nucleotides that have no or limited coding capacity. Long intervening/intergenic noncoding RNAs (lincRNAs) are sequences of lncRNA which do not overlap protein-coding genes.

<span class="mw-page-title-main">Small nucleolar RNA SNORD113</span>

In molecular biology, Small nucleolar RNA SNORD113 is a small nucleolar RNA molecule which is located in the imprinted human 14q32 locus and may play a role in the evolution and/or mechanism of the epigenetic imprinting process.

A conserved non-coding sequence (CNS) is a DNA sequence of noncoding DNA that is evolutionarily conserved. These sequences are of interest for their potential to regulate gene production.

An ultra-conserved element (UCE) was originally defined as a genome segment longer than 200 base pairs (bp) that is absolutely conserved, with no insertions or deletions and 100% identity, between orthologous regions of the human, rat, and mouse genomes. 481 ultra-conserved elements have been identified in the human genome. If ribosomal DNA are excluded, these range in size from 200 bp to 781 bp. UCRs are found on all chromosomes except for 21 and Y. A database collecting genomic information about ultra-conserved elements (UCbase) is available at http://ucbase.unimore.it.

Donna R. Maglott is a staff scientist at the National Center for Biotechnology Information known for her research on large-scale genomics projects, including the mouse genome and development of databases required for genomics research.

References

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