DUF1220-domain copy number implicated in human brain-size pathology and evolution
Laura J Dumas1, Majesta S O'Bleness, Jonathan M Davis
1Department of Biochemistry and Molecular Genetics and Human Medical Genetics and Neuroscience Programs, University of Colorado School of Medicine, Aurora, CO 80045, USA.
American Journal of Human Genetics
|August 21, 2012
Summary
DUF1220 gene copy number variations are linked to brain size differences. Loss of DUF1220 copy number is implicated in microcephaly, highlighting its role in brain development and evolution.
Area of Science:
- Genetics
- Neuroscience
- Evolutionary Biology
Background:
- DUF1220 domains exhibit significant human-lineage-specific copy number increases.
- These domains are located at 1q21, a region associated with microcephaly and macrocephaly.
- DUF1220 copy number strongly correlates with brain size across primate species.
Purpose of the Study:
- To investigate the role of DUF1220 domains in 1q21-associated brain size pathologies.
- To determine the association between DUF1220 copy number and brain size in individuals with microcephaly and macrocephaly.
Main Methods:
- Utilized specialized bioinformatics tools for analyzing highly duplicated DUF1220 sequences.
- Implemented targeted 1q21 array comparative genomic hybridization in individuals with 1q21-associated brain size abnormalities.
- Examined 53 genes at the 1q21 locus and assessed correlations with brain size metrics.
Main Results:
- DUF1220 copy number showed the strongest association with brain size in individuals with 1q21-associated microcephaly, particularly conserved clades CON1, CON2, and CON3.
- NBPF family genes within 1q21 showed correlations with frontal-occipital-circumference Z scores in the deletion group.
- In a general population, DUF1220 copy number correlated most strongly with brain gray-matter volume.
Conclusions:
- Loss of DUF1220 copy number is strongly implicated in the etiology of 1q21-associated microcephaly.
- DUF1220 domains are key effectors influencing evolutionary, pathological, and normal variations in brain size.
Related Concept Videos
02:37Gene Duplication and Divergence
The seminal work of Ohno in 1970 popularized the idea of gene duplication and divergence. DNA sequence comparison studies reveal that a large portion of the genes in bacteria, archaebacteria, and eukaryotes was generated by gene duplication and divergence, indicating its critical role in evolution.
The duplicated copies of the gene are called Paralogs. Paralogs with similar sequences and functions form a gene family. Across several species, a large number of gene families are characterized.
The duplicated copies of the gene are called Paralogs. Paralogs with similar sequences and functions form a gene family. Across several species, a large number of gene families are characterized.
02:26Comparing Copy Number Variations and SNPs
Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...
03:21Genome Size and the Evolution of New Genes
While every living organism has a genome of some kind (be it RNA, or DNA), there is considerable variation in the sizes of these blueprints. One major factor that impacts genome size is whether the organism is prokaryotic or eukaryotic. In prokaryotes, the genome contains little to no non-coding sequence, such that genes are tightly clustered in groups or operons sequentially along the chromosome. Conversely, the genes in eukaryotes are punctuated by long stretches of non-coding sequence.
03:21Genome Size and the Evolution of New Genes
While every living organism has a genome of some kind (be it RNA, or DNA), there is considerable variation in the sizes of these blueprints. One major factor that impacts genome size is whether the organism is prokaryotic or eukaryotic. In prokaryotes, the genome contains little to no non-coding sequence, such that genes are tightly clustered in groups or operons sequentially along the chromosome. Conversely, the genes in eukaryotes are punctuated by long stretches of non-coding sequence.
02:05Chromosome Duplication
The process of chromosome duplication during cell division requires genome-wide disruption and re-assembly of chromatin. The chromatin structure must be accurately inherited, reassembled, and maintained in the daughter cells to ensure lineage propagation.
The basic unit of the chromatin is the nucleosome, consisting of DNA wrapped around octameric histone proteins and short stretches of linker DNA separating individual nucleosomes. The histone proteins within the nucleosome have their...
The basic unit of the chromatin is the nucleosome, consisting of DNA wrapped around octameric histone proteins and short stretches of linker DNA separating individual nucleosomes. The histone proteins within the nucleosome have their...
01:43Incomplete Dominance
Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.