Week 6 - Human genome variation Flashcards
Define the following terms:
Locus
Allele
Homozygote
Heterozygote
Hemizygote
Locus
* the chromosome location of a specific gene
Allele
* The different forms of a gene or DNA sequence
Homozygote
* An individula in whom the two alleles at a locus are the same
Heterozygote
* An individual who has two different alleles at a locus
Hemizygote
* An individual who has unpaired genes in an otherwise diploid cell (e.g. X-linked genes in
males)
Locus vs Allele on a picture?
Allele vs gene on a picture
Explain the terms
Wild type and variant
Wild-type
* single prevailing allele, usually present in more then half of the individuals. The most common allele.
Variant
* the other version of the allele that differ from wild-type allele due to permanent changes in
nucleotide sequence or arrangement in DNA sequence
Changes on nomenclature, based on HGVS
- old term: mutation
- new term: sequence variant, allelic variant, alteration or change
What is SNP
SNP stands for “single nucleotide polymorphism”.
is a sequence variant/allelic variant/alteration/change
Alteration in human genome can be observed in different level:
Alteration in human genome can be observed in different level:
* chromosomal aberrations – numerical and structural
* alteration of DNA sequence
Mutation can affect somatic cells (may accumulate, may lead to cancer development) and germline
cells (can be transmitted from one generation to the next)
Chromosomal abberations vs DNA alterations
Comparison in
changes, scale and damage
Origin of genetic variation – spontaneous
Spontaneous process of mutation:
◦ errors in DNA replication – the most common source. It is prevented by DNA
polymerase “proofreading” activity
◦ small numbers of extra nucleotides being inserted into synthesized polynucleotide or some nucleotides in the template not copied
- repeated units (microsatelites) of DNA sequence may result in replication slippage
- errors in DNA reparation
- Errors in recombination during the cell division (meiosis
- errors in cell division
Replication basically. 3 types.
Origin of genetic variation – induced
Origin of genetic variation – induced
* Induced process of mutation by environmental factors
* physical – ionized radiation, UV. UV-induced dimerization usually results in a deletion when the modified strand is copied
* chemical – oxidative stress, aromatic amines, deaminating agents etc. Deamination results in point mutations (single nucleotide change) when the template strand is copied
* biological – transponsons (the jumping gene), viruses
Induced. Outside the cell. 3 types.
Variation in human genome
Type of variation, alleles, molecular mechanism
5
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Type of allelic variants and their consequences
Base substitution:
Missense
– single nucleotide substitution in coding region, which alters the genetic code by
nonsynonymous replacement of one amino acid
Silent
– Single nucleotide substitution in coding region, which alters the genetic code by
synonymous replacement of one amino acid (amino acid is not changed)
Nonsense
–Single nucleotide substitution in coding region, which alters the genetic code by
producing on of the three stop codons (UAA, UAG or UGA) in the mRNA
Affecting RNA transcription, processing and translation – e.g. splice sit mutation – occur at exon-intron or intron-exon boundaries, alter the splicing signal that is necessary for proper excision of an intron
Deletions – loss of one or more base pair
Insertions
– insertion of one or more base pair
- Deletions and insertions tend to be especially harmful when the number of missing or extra base pairs is not a multiple of three. It may lead to the sift of reading frame and alter all of the downstream/upstream codons – frameshift mutation
Insertion of mobile elements
– insertions of LINE and SINE (Alu) repeats can cause frameshift mutations and are described in context of human pathology
Dinamic mutation
– involve amplification of a simple nucleotide repeat sequence (eg.
[CGG]n, [CAG]n). Usually repeats expanding during gametogenesis
Consequences of allelic variants in functional level
Gain-of-function: allelic variant lead to completely new protein product (with new function) or overexpression of product, or inappropiate expression (wrong time, wrong place etc.)
Loss of function: loss of gene product activity
Dominant negative: the abnormal protein product interferes with the normal protein product
and inhibits its function
Numerical abberations
Aneuploidy and Polyploidy
Polyploidy: one extra in EVERY chromosome set
Aneuploidy: One extra in one set of chromosome. Eg Downsyndrome. 3 chromosomes in number 21.
Structural aberrations
Structure är FOOKED in chromosome.
balanced: påverkar ej ex inversion.
Unbalanced: big change in chromosome structure eg remove or add new sequences within chromosome structure.
is the rearrangement of structure or regional organization of chromosomes. This type of alteration of chromosome structure can occur when homologous chromosomes line up improperly during cell division.
Chromosome breakage occur during cell division. There are mechanisms which can repair this form of breaks, but sometimes the breaks remain or they heal in a fashion which alters the structure of chromosome.
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