CM09-Mutations and polymorphisms

Locus (loci)

DNA segment that occupies a specific position on a chromosome

Alleles

Alternative versions of DNA sequence at a specific locus

Wild-type/common allele

Most genes have one prevailing allele

Variants/mutants

All other versions of alleles

Polymorphic

A locus with >2 common alleles

Private alleles

Rare variants confined to families

Zygosity

Degree of allele similarity at one locus in an organism

Homozygous

2 copies of same allele at one locus

Heterozygous

2 different alleles at same locus

Genotype

Genetic information at a locus

Phenotype

Appearance of an organism based on genotype

Mutations

Source of genetic diversity

Genetic variability

0.1% = genetically determined variability among individuals

GWAS

Genome-Wide Association Studies

Genotype imputation

Process based on linkage disequilibrium

SNP detection

Steps in identifying single nucleotide polymorphisms

Personalized medicine

Role of SNPs in tailoring medical treatment

Reference sequence

The most common sequence in a population.

Euploidy

Multiplication of a chromosome set (tetraploidy).

Aneuploidy

Additional chromosomes (trisomy, monosomy).

Mutation frequency

Number of mutations/locus/cell division dependent on frequency of spontaneous and induced nucleotide changes, probability of repair, and probability of detection.

Mutation rates

Vary among genes and species.

Hot spots

Areas of DNA that mutate differently.

Rate of disease-causing mutations

Incidence of new cases of genetic disease NOT present in parents and caused by a single mutation.

Chromosome mutations

Result of chromosome mis-segregation during meiosis, generally severe, resulting in spontaneously aborted fetuses.

Regional mutations

Result of homologous recombination between fragments with high homology at different sites or following repair of double-strand breaks.

Gene mutations

Replication errors <1 mutation/genome/cell division, frequently from spontaneous mutations that evade the repair machinery.

Nucleotide substitutions

Changes in nucleotides that can result in synonymous mutations, missense mutations, or nonsense mutations.

Synonymous mutations

Nucleotide change that specifies the same amino acid (AA).

Missense mutations

Single nucleotide change that specifies a new AA.

Nonsense mutation

Point mutations resulting in replacement of coding codon by a 'stop' codon.

Mutation affecting mRNA processing

Mutations that abolish or create alternative intron-exon junctions, altering the splicing pattern.

Dynamic mutations

Amplifications of simple trinucleotide repeats in the coding region or untranslated regions.

Frameshift mutations

Rearrangement of a small number of nucleotides (not a multiple of 3) resulting in altered reading frame, leading to functionally altered protein.

Gain-of-function

Overproduction or inappropriate production of protein.

Loss-of-function

Reduced production of protein.

Haploinsufficiency

If 50% of protein is insufficient for function.

Dominant negative

Mutated protein inhibits the product of the normal allele in heterozygosity.

Germline mutations

Mutations inherited from parents or de novo mutations that are transmitted to offspring.

Somatic mutations

Mutations that are not transmitted to the next generations and are frequent in cancers.

Genetic polymorphisms

Mutations with a frequency exceeding 1% of all alleles in a population.

Single nucleotide polymorphisms (SNPs)

Change of 1bp, average 1 for every 1000bp (approx. 5-10 million SNPs/genome), generally do not produce phenotypic differences.

SNP hot spots

25x higher rate at adjacent CG (CpG).

SNPs in protein-coding genes

Approx. 100,000 SNPs.

Synonymous SNPs

Do not change the amino acid sequence of the protein.

Nonsynonymous SNPs

Result in protein variants.

Insertion-deletion polymorphisms (indels)

Up to 1000bp, presence or absence of a short fragment results in 2 alleles.

Microsatellites

Variable number of repeated short segments (2, 3, or 4 nt) resulting in multiple alleles.

DNA fingerprinting

Infer familial relationships by studying alleles at 13 loci.

Copy number variants (CNVs)

Up to hundreds of kb, can include dozens of genes and alter gene dosage.

Inversion polymorphisms

Few bp to mb, characterized by sequence homology at edges (homologous recombination).

Balanced inversion polymorphisms

No loss/gain of DNA.

Discovery process in genetic analysis

Initial identification through whole genome/whole exome sequencing and comparison to reference sequence.

Validation process in genetic analysis

Replication assay to exclude sequencing errors and larger population to get statistical occurrence.

Screening process in genetic analysis

Sequencing/analysis of thousands of SNPs from same individual and multiple individuals using high-density DNA arrays (SNP arrays).

Genome-wide association studies (GWAS)

Molecular technique that analyses hundreds of thousands (even millions) of variations in genomic DNA to determine if a genetic locus is associated with a certain phenotype.

Candidate gene associations

Have greater power but rely on previous knowledge.

SNP imputation

Genotyped SNPs allow for determining possible variants on neighboring SNPs based on reference genomes (HapMap).

Linkage disequilibrium

Non-random association of alleles at linked loci.

Haplotypes

Sets of closely linked SNPs present on the same chromosome, which tend to be inherited together.

Manhattan plot

Scatter plot of association between statistical significance as p-value on the y-axis against chromosomes on the x-axis.

p-value

Considered statistically significant if p=5x10-8.

SNP

Single Nucleotide Polymorphism; a variant that may be significantly associated with a phenotype.

Clinically functional variants

Variants that have a direct impact on disease risk.

Risk variants

Genetic variants that increase the risk of disease.

Protective variants

Genetic variants that lower the risk of disease.

Personal direct-to-consumer genomics

Testing of genome-wide polymorphisms by companies like 23andme.

Cilantro aversion

A trait tested in direct-to-consumer genomics.

Caffeine metabolism

A trait tested in direct-to-consumer genomics.

Carrier status

Information about genetic conditions such as cystic fibrosis and sickle cell anemia.

Ancestry

Information about ancestral composition and lineage.

AAO recommendations

Guidelines for genetic testing for eye disease established in 2013.

Environmental role

The influence of environmental factors on gene-disease associations, which is often unknown and hard to predict.

Gene-disease associations

Relationships between specific genes and diseases that may not be relevant for all patients.

Combined risk from multiple SNPs

The challenge of calculating the overall risk from various genetic variants.

Avoid direct-to-consumer genetic testing kits

Recommendation to provide patients with information to seek approved testing facilities.

Order the most specific genetic test

Guideline to choose tests based on the patient's clinical findings.

Avoid repetitive testing

Recommendation against repeated tests for complex genetic diseases without a clear treatment plan.

Testing of asymptomatic minors

Should be avoided unless all parents consent or justifiable cause is established.

Clinical utility/limitations

The relevance of genetic testing for prognosis can be affected by confounding factors.

Eye color genes

Genes associated with eye color include ASIP, HERC2, IRF4, MC1R, OCA2, TYP, TYRP1, SLC24A5.