--- module: 092-01 language: en chapter: 92 title: "Chromosomes, Human Variation, Population Genetics, and Genomic Methods" module_title: "Chromosomes, meiosis, Mendelian inheritance, mosaicism, penetrance, and pedigrees" source_sha256: 788b17e2d98e9d91483858b8d0ad1605aedc90a3c264fe4d87b724ef84914e8d --- # Chromosomes, meiosis, Mendelian inheritance, and pedigrees ## Framing and chromosome structure ### Many mechanisms of genetic disease #### Single nucleotides, copy number, rearrangements, repeats #### Mitochondrial variants, epigenetic errors ### Inheritance is transmission, not mechanism or severity ### 22 autosome pairs plus two sex chromosomes ### Sister chromatids joined at the centromere #### Telomeres cap ends, kinetochore binds spindle ### Band address runs outward from the centromere ### Genomic coordinates need the assembly version ## Meiosis and aneuploidy ### Homologues pair and recombine at chiasmata ### Homologues split in meiosis one, chromatids in two ### Nondisjunction yields aneuploid gametes #### Trisomy or monosomy after fertilisation #### Mitotic error after fertilisation gives mosaicism ### Phenotype: chromosome, fraction, tissue, dosage ### Most monosomies and many trisomies are lethal #### Viable: trisomy 21, 18, 13 and sex chromosomes ### Maternal age: arrested oocytes lose cohesion ### Paternal age: new variants via spermatogonial divisions ## Polyploidy and structural rearrangement ### Triploidy from two sperm or a diploid gamete #### Parental origin shapes placenta and fetus ### Tetraploidy lethal unless mosaic ### Balanced: no major net copy-number change #### May disrupt a gene or regulatory domain #### Can create unbalanced gametes ### Unbalanced: dosage change and phenotype ## Translocations, inversions, rings ### Reciprocal: exchange between nonhomologues ### Robertsonian: fused acrocentric long arms #### Miscarriage or translocation trisomy #### Recurrence differs from free trisomy, test parents ### Inversion rotates a chromosome segment #### Paracentric excludes centromere, pericentric includes #### Loop recombination yields abnormal products ### Ring from terminal breaks and fusion ### Isochromosome: one arm duplicated, other lost ## Autosomal inheritance ### Dominant: vertical, all sexes, one-half risk #### De novo variant gives an isolated case #### Reduced penetrance mimics a skipped generation #### Haploinsufficiency, dominant negative, gain, toxicity ### Recessive: variants in both gene copies #### Carrier parents, one-quarter sibling risk #### Consanguinity raises shared rare alleles #### Compound heterozygosity: two different variants #### Pseudodominance where the allele is frequent ## Sex-linked and mitochondrial inheritance ### X-linked recessive affects hemizygous males #### No father-to-son transmission #### Symptomatic females: skewing, dosage, tissue ### X-linked dominant: father to all daughters #### Heterozygous mother: one-half to each child ### Pseudoautosomal genes recombine ### Mitochondrial DNA is maternally inherited #### Heteroplasmy: normal and variant genomes coexist #### Bottleneck, segregation, thresholds vary severity ## Imprinting and repeat expansion ### Expression depends on parent of origin ### Uniparental disomy: both homologues from one parent #### Imprinting disease or unmasked recessive ### Imprinting-centre and methylation defects mimic deletion #### Recurrence follows mechanism, not syndrome name ### Anticipation: earlier or more severe each generation #### Repeats expand during gametogenesis #### Coding CAG expansion gives polyglutamine #### Noncoding expansion silences genes or alters RNA ## Penetrance, heterogeneity, mosaicism ### Penetrance: proportion affected by a set age ### Expressivity: degree or pattern among affected ### Modifiers, environment, ascertainment alter both #### Clinic estimates may not fit screening ### Pleiotropy, locus and allelic heterogeneity ### Phenocopy from a non-genetic cause ### Mosaicism from postzygotic change #### Earlier events involve more tissues #### Gonadal mosaicism: repeated affected children #### Low-level mosaicism missed in blood ## Pedigrees and counselling ### Record three generations when possible ### Respectful language and confidentiality ### Bayesian update of prior risk #### Negative result limited by assay sensitivity #### Young unaffected status is weak evidence ### Transmission, disease risk, severity are distinct ### Discordance prompts reconsideration #### Phenotype, mosaicism, penetrance, second diagnosis