Same-chromosome alleles or RFLP markers tend to inherit together {linkage}| {genetic linkage} {linkage group} in meiotic recombination, mitotic replication, and prokaryote binary fission. Closer markers are less likely to separate during DNA recombination and so are more likely to inherit together. Linkage frequency depends on distance between loci.
finding distance from linkage
Known genetic linkages show relative loci distances. Distances are in centimorgans. Markers less than five centimorgans have less than 1 in 20 chance to separate.
Alleles at neighboring genetic loci can more frequently associate than expected from allele frequency and genetic linkage {linkage disequilibrium} {allelic association}. Algorithms can identify linkage disequilibrium.
Units {centimorgan} (cM) can measure recombination frequency. One centimorgan is 1% chance that, at one crossing over, marker at one genetic locus separates from marker at second locus. In humans, one centimorgan is one million base pairs.
Chromosomes have gene locations {DNA mapping}.
chromosome separation
Cell-sorting machines can sort chromosomes. Alternatively, people can separate chromosomes using microscopes and fine instruments. Human cells treated with x-rays can fuse with mouse cells to isolate chromosome pieces, to map with markers {radiation hybrid mapping}. Two-dimensional electrophoresis using variable fields can separate DNA fragments up to three million bases {pulsed field gel electrophoresis} (PFGE), over several days.
protein removal
Proteolytic enzymes remove protein from chromosomes held in gels, leaving DNA.
DNA fragments
NotI, MluI, NruI, and SfiI restriction enzymes have eight-base sites and cut DNA in few places, to make million-base DNA fragments.
methylation
Tissues can have methylated sites, allowing fewer cuts and larger fragments, so researchers must compare different tissues. Large fragments have further processing.
cloning
YACs allow cloning hundred-kilobase DNA fragments. Phages and cosmids allow cloning 40000-base DNA fragments, for genomic libraries.
separation
From clones, electrophoresis separates restriction fragments by size.
markers
Genetic markers can find loci.
hybridization
20-base oligonucleotide probes can hybridize with DNA. Probes can have minor-groove binder to enhance exact hybridization, allowing shorter probes. Probes hybridize with clone DNA fragments. Overlapping DNA fragments hybridize to same probe. Clone-fragment sequence-tagged connector ends hybridize to probes.
sites
Using unique primers, processing identifies unique 200-base to 500-base sequence-tagged sites, which have known locations.
overlapping
DNA fragments overlap to build longer sequences {contig, DNA}, to sequence chromosome DNA.
Neutral or disadvantageous gene mutations can survive if they are adjacent to advantageous genes {hitch-hiking natural selection}.
Complex genetic diseases divide into different onset ages and/or different disease severities {liability class}. This can increase genetic-linkage information by accounting for phenocopy traits, whose appearances are similar but have different causes. Categories have different phenocopy rates. Phenocopy rates increase as onset age increases and as severity decreases.
Genes and other markers are at relative or absolute chromosome positions {locus, gene}| {loci} {genetic locus}.
Individual marker traits have probabilities. Probabilities differ for linkage or no linkage. Values {LOD Score} can measure linkage degrees in families by estimating recombination fraction: base-10 logarithm of ratio between probability assuming linkage and probability assuming no linkage. In LOD-score analysis, disorders can make complex patterns.
Testing father, mother, and child to establish genetic linkage and association {Transmission Disequilibrium Test} (TDT) can find linkage disequilibria.
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Date Modified: 2022.0225