lecture 20- mapping disease through mendelian approaches Flashcards
human genome project
launched in 1990 to sequence the first complete human genome
massive parallel methods (next gen sequencing)
revolutionizing sequencing providing faster and cheaper genomes
genome centers
operate highly automated production lines, increasing genomic output
snp (single nucleotide polymorphisms)
places where 1 base pair is different (changes amino acids, changes protein)
ex: glutamic acid to valine causes sickle cell
short tandem repeats (genetic markers)
regions in the genome where there are many repeats
ex: over 30 CAG repeats- huntington (repeats are likely to make mutations because there are so many similar things)
copy number variants
long region of the genome where you may have different numbers of copies
ex: alpha thalassemia
cystic fibrosis
Cystic fibrosis (CF) is a genetic disorder that causes problems with breathing and digestion. CF affects about 35,000 people in the United States. People with CF have mucus that is too thick and sticky, which. blocks airways and leads to lung damage; traps germs and makes infections more likely
each person has a gene called
CFTR. That gene encodes a protein that functions as a channel that
allows chloride ions to travel across cell membranes. When a mutation
occurs that inactivates the CFTR gene, the protein no longer performs its
function, causing improper ion concentrations inside and outside their
cells. Thus, a person with CF does not properly produce sweat, digestive
juices, and mucus.
breakthroughs in diagnosis and etiology of cf
cftr (cystic fibrosis gene)
How many genes do we have
20,000
mendelian genetics approach to disease mapping
uses small datasets to investigate single gene/simple traits
population genetic approach to disease mapping
uses large datasets to investigate complex traits
why cant qtl mapping be done in humans
cant ethically do a backcross or intercross unlike fruit flies
steps of a linkage analysis study
STR (short tandem repeats)
useful for linkage analysis as they are highly polymorphic
how do we genotype strs
by measuring length of dna bands with gels after pcr
why can bi-allelic markers sometimes lead to uninformative crosses
steps of a lod score calculation
informative parent
heterozygote (assuming pedigree is informative) for both the trait and the marker
*other parent must be homozygous
phase
the arrangement of trait and marker alleles (which allele combinations are present on each homolog in the parents alleles)
lod score
measures the likelihood that each dna site being tested is linked to the site responsible for the disease
calculating lod score
Autosomal dominant
Autosomal dominant is a pattern of inheritance characteristic of some genetic disorders. “Autosomal” means that the gene in question is located on one of the numbered, or non-sex, chromosomes. “Dominant” means that a single copy of the mutated gene (from one parent) is enough to cause the disorder.
The key components of disease mapping using LOD score analysis are as
follows
- Pedigrees (generated in hospitals): Choose a family and determine
whether each person has the disease or not - Genotyping (performed in labs): Determine which allele each
person has at many sites (marker loci) in the genome - LOD score calculations (performed using computers): Identify the
site that is most correlated with presence/absence of the disease
benefits of using str as marker
A benefit of using STRs is that they tend to be very variable; therefore, many different alleles are possible. This means that it is very likely that any individual in a pedigree will be heterozygous at the STR locus. This makes it easier to track inheritance of a specific allele throughout the pedigree. If the parents are both heterozygous, we can say with confidence which allele each child inherited from each parent. If the parents are homozygous, it becomes unclear which allele they passed on to each child, making the site less informative.
A LOD score less than 0
indicates
that the marker and locus of interest are more likely to be
assorting independently than they are to be linked at the tested
recombination frequency. Note that this does not necessarily mean that
they are not linked, only that they are not likely to be linked at the
recombination frequency that you tested
what does the marker that gives the highest LOD score tell us
where to look for our site of interest
