Mammalian Genome Variation

Genome Variation and Karyotypes

• Mammals have varying karyotypes and genome sizes, but a similar number of genes, which make up approximately 1-2% of the genome.
• Genome variation can be classified into five categories: single nucleotide variants (SNVs), small insertions and deletions (indels), structural variants, transposable element insertions, and cytogenetic variants.

Types of Genome Variation

• Single nucleotide variants (SNVs): the mutation of a single DNA base into a different base.
• Small insertions and deletions (indels): insertions and deletions less than 100 base pairs in length, frequently caused by polymerase slippage.
• Structural variants: large-scale DNA mutations that juxtapose DNA that was previously not connected, can be inter-chromosomal or intra-chromosomal.
• Transposable element insertions: autonomous (encode the machinery needed for transposition) or non-autonomous (use the transposition machinery of a different class of transposable element).
• Cytogenetic variants: the gain or loss of one or more entire chromosomes, causing aneuploidy.

Effects of Genome Variation

• Most genome variation is non-pathogenic, but a small subset of genetic variants cause or contribute to disease.
• Genome variation can be caused by exogenous or endogenous mutational processes.
• Unbalanced structural variants can lead to copy number variation.

Genome Analysis and Repair

• Genome variation is discovered by whole genome sequencing, which involves shearing DNA into small segments and aligning these to the reference genome.
• The cell has DNA repair mechanisms, and those genome variants that we observe are those that escape repair.
• Genome variation can be germline (inherited) or somatic (private to the individual).

Glossary

• Genome: the entirety of genetic material (DNA) within a cell or organism.
• Karyotype: the set of chromosomes within a cell.
• Autosome: any chromosome that is not a sex chromosome.
• Telomere: the sequence structure at the end of chromosomes.
• Centromere: the region of the chromosome that attaches to the mitotic spindle, and the region where two sister chromatids are joined.
• Reference genome: a completely sequenced genome isolate from a particular species that is used as a reference for genome analysis.
• Genotype: the genetic constitution of a particular individual.
• Phenotype: the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment.
• Locus: a specific fixed genomic position in the genome where a particular gene or genetic marker is located.
• Allele: a variant form of a sequence present at a particular locus.
• Linkage: two loci which are located close together on the same chromosome and which are frequently inherited together.

Genome and Chromosomes

• Genome: the entirety of genetic material (DNA) within a cell or organism
• Karyotype: the set of chromosomes within a cell
• Diploid: two copies of each chromosome are present
• Tetraploid: four copies of each chromosome are present
• Autosome: any chromosome that is not a sex chromosome
• Sex chromosome: X and Y chromosomes (in mammals)

Chromosome Structure

• Telomere: the sequence structure at the end of chromosomes
• Centromere: the region of the chromosome that attaches to the mitotic spindle, and the region where two sister chromatids are joined
• Sister chromatids: identical copies of a duplicated chromosome, joined at the centromere

Genome Analysis

• Reference genome: a completely sequenced genome isolate from a particular species that is used as a reference for genome analysis
• Genotype: the genetic constitution of a particular individual

Characteristics and Variations

• Phenotype: the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment
• Locus (plural loci): a specific fixed genomic position in the genome where a particular gene or genetic marker is located
• Allele: a variant form of a sequence present at a particular locus
• Linkage: two loci which are located close together on the same chromosome and which are frequently inherited together

Mutations

• Single nucleotide variants (SNVs): the mutation of a single DNA base into a different base
• Exogenous mutational process: a process that leads to mutations that arises from exposure to exogenous agents, such as cigarette smoke carcinogens or ultraviolet light
• Endogenous mutational process: a process that leads to mutations that arises from exposure to natural processes that occur within the cell, such as spontaneous deamination of 5-methylcytosine
• Small insertions and deletions (indels): a mutation that involves insertion or deletion of a small sequence of DNA bases