Lecture 18: Medical Genetics- Consequences and genomics Flashcards
What is a genetic mutation?
- Any permanent heritable changes in the sequence of genomic DNA
- Any alteration in DNA from its natural state: may be disease-causing or benign normal variant
What is a genetic polymorphism?
- The occurrence together in a population of two or more alternative genotypes, each at a frequency greater than that which could be maintained by recurrent mutation alone.
- Natural variations in genomic DNA sequence, that usually have no obvious adverse effects on the individual and occur with fairly high frequency in the general population.
What are the types of mutations?
- Silent; Single base change, no AA change (triple code degenerency)
- Missence; Single base change, changes AA, may or may not cause abnormal phenotype.
- Nonsense; Single base change, changes AA to stop codon.
- Frameshift; Insertion or deletion of bases in anything other than 3’s
- Splice donor/acceptor; Alteration of sequences for accurate splicing of introns.
- Indel; A mutation that involves the insertion or deletion of bases - can (but not always) cause a frameshift.
How can we decide if a DNA change is pathogenic?
- If a missence, is it at a functionally import. site?
- Is encoded protein truncated?
- Is RNA splicing affected?
- Does the change segregate with disease in the family?
What is a somatic vs germline mutation?
Somatic = Non-gamete forming cell mutation, not heritable
Germ line = Mutation in a cell ultimately forming gamete, heritable
What are the possible phenotypic consequences of mutations?
1) Loss of function mutations
2) Gain of function mutations
Write some notes on loss of function mutations;
- Produce either a reduced amount or reduced activity of the gene product
- Usually have minimal effect on phenotype unless both alleles affected
- Absence of normal gene product or function = Null allele
- 50% gene product, altered phenotype = Haploinsufficiency
- Dominant negative effect (abnormal product interferes with product from other normal allele) (heterozygous loss of function mutations)
What is a gain of function mutation?
Produce either an increased amount or increased activity of the product
Whats the purpose of a pedigree tree?
To identify inheritance single gene disorders.
- Autosomal
- X chromosomal
- Y Chromosomal
What are the pedigree symbols? Refer to book… also make another card
Square = Male Circle = Female Diamond = unknown gender Filled circle = affected Square with black dot = obligate carrier Single line = union Double line = Consanguinity
What are the mendelian patterns of inheritance?
- Autosomal dominant
- Autosomal recessive
- X-linked recessive
- X-linked dominant
- Y-linked (holandric)
What is an allele?
Alternative form of a gene. (wild type = normal)
What is lyonisation?
Random inactivation of parts of one x chromosome in female somatic cells. This is the basis of a manifestation heterozygote, where a female heterozygous for a sex-linked recessive mutant gene expresses the same phenotype as a male hemizygous for the mutation.
What are complications to the basic mendelian pedigree pattern;
- Common recessive conditions can give psuedo-dominant pattern
- Non-penetrance
- Variable expression (including anticipation)
- New mutations / germline mosaicism
What is allelic heterogeneity;
Different mutations at the same locus (same gene)
i.e cystic fibrosis >1000 mutations in CFTR gene
