Biology1A03: Theme 5 Module 3

11/27/25, 3:07 AM Biology1A03: Theme 5 Module 3 2025. 11. 26. 8:02 Biology 1A03 Theme 5: The Principles of Inheritance Module 3: Sex Chromosomes and Linkage Pedigrees and human trait inheritance While peas were convenient for Mendel, inheritance of human traits is more complicated Humans do not produce many offspring Not ethical to ask humans to breed for observation Geneticists use family history to track traits They build a family tree (pedigree) to visualize the segregation of a trait In a pedigree: Males = squares Females = circles Affected individuals = shaded symbols unspecified = diamond Matings are shown as: One horizontal line between unrelated individuals Two horizontal lines between related individuals Arranged horizontally Birth order shown from left to right Pedigrees allow tracking of dominant and recessive inheritance patterns X-linked / autosomal These patterns mirror what Mendel observed in pea plants 11/27/25, 3:07 AM Genes on chromosomes & recombination Humans have 23 pairs of chromosomes Human genome contains over 3 billion base pairs Sequencing of the human genome shows: More than 20,000 protein-coding genes Plus additional functional RNA genes Therefore, each chromosome must contain multiple genes Mendelian inheritance alone is not sufficient to explain all inheritance patterns Key question: Are all alleles on one chromosome inherited together as a single unit or can they separate​? Observed phenotypic variation in plants and animals suggests: Alleles linked on the same chromosome can become unlinked New allele combinations occur through recombination Unit 1:The Inheritance of Gene on the X Chromosome Chromosomal basis of sex determination Although males and females differ anatomically and physiologically chromosomal basis of sex is unique Humans and other mammals have ​two sex chromosomes: X and Y The Y chromosome is much smaller than the X chromosome Females = XX (one X from each parent) Males = XY develop from a gamete carrying an X and a Y chromosome 11/27/25, 3:07 AM Most regions of the X and Y chromosomes are non-homologous Means most genes on X have no counterpart As a result, recombination does not occur between most of the X and Y Only small regions at the tips of X and Y are homologous These regions allow X and Y to pair and segregate like homologous chromosomes during meiosis Sequencing of the human Y chromosome reveals: 78 genes Code for about 25 proteins Half of these genes contribute to sex determination The X chromosome ~1100 genes Many have functions unrelated to sex A gene located on either sex chromosome is called a sex-linked gene Expression of these genes may depend on the sex of the individual Inheritance of sex chromosomes Following the inheritance of the sex chromosomes shows how genes on X and Y determine sex Females = XX Males = XY In humans, genes on the Y chromosome trigger a cascade that leads to the ​male phenotype Autosomes are inherited normally but are not shown in the figure Autosomes= sex gene Because sex is determined by the father’s chromosome: 50% chance a child inherits the Y → male 11/27/25, 3:07 AM 50% chance a child inherits the X → female The mother always passes on an X chromosome Mendel’s inheritance patterns hold for many genes Because pea plants lack sex chromosomes X-linked inheritance & red/green color-blindness Inheritance of X-linked alleles​in humans can be followed using pedigrees Pedigrees track grandparents → parents → children across multiple generations Example trait: red/green color-blindness A recessive X-linked disorder Caused by an X-linked gene on the X chromosome Ishihara color test detects red/green color-blindness Uses colored dot patterns forming numbers Visible to individuals with normal vision Difficult or invisible to color-blind individuals Inheritance pattern Since the trait is recessive, a woman must be homozygous (XªXᵃ) for the color-blindness allele to show the phenotype A heterozygous woman (XᴬXᵃ) is a carrier Not show color-blindness Can pass the allele to her children Any male who receives the recessive allele from his mother will be color-blind Males have only one X chromosome Only one locus for this allele A male with one recessive allele is hemizygous Hemizygous = only one copy of a gene present In hemizygous individuals, dominant/recessive rules do not apply A male will express whichever allele is present on his single X chromosome Probability of inheriting an X-linked recessive allele By Mendelian inheritance, there is a ​50% chance of passing on the color-blindness allele Example: a female with One affected X allele (red line, Xᴺ) One normal X allele (black line, Xᶜ) She is a carrier, not color-blind because the trait is recessive Each offspring has a 50% chance of inheriting either the normal or affected allele Males are hemizygous for X-linked genes They express whichever allele is on their single X chromosome A male inheriting the affected allele → color-blind Female offspring have a 50% chance of inheriting the affected allele Will not show the phenotype (they would be carriers) 11/27/25, 3:07 AM A Punnett square shows these probabilities clearly: Carrier mother (XᴬXᵃ) × Normal father (XᴬY) Sons: 50% normal, 50% color-blind Daughters: 50% normal, 50% carriers X-linked recessive traits & carrier females (Hemophilia example) Pedigrees allow tracking of female carriers across many generations These women are heterozygous for the recessive allele They do not show the phenotype Called: hidden carrier They can pass the allele to their sons with a 50% probability Hemophilia is an X-linked recessive disorder Caused by a mutation in a gene required for blood clotting Queen Victoria was a carrier for the hemophilia allele She had a son affected by hemophilia She introduced the allele into the British Royal Family In the pedigree shown: Carrier females are indicated They are heterozygous individuals They can pass the affected allele to offspring following Mendelian principles 11/27/25, 3:07 AM Hemophilia inheritance from Queen Victoria Queen Victoria was the first British Royal family member with a son affected by hemophilia We can analyze the possible genotypes of her offspring with Prince Albert using a Punnett square Punnett square results: ½ of daughters = carriers ½ of daughters = normal ½ of sons = normal ½ of sons = affected by hemophilia Therefore: A carrier mother has a 50% chance of having a carrier daughter A carrier mother has a 50% chance of having an affected son It is rare for a female to have hemophilia She must inherit the affected allele from both mother and father Hemophilia became widely known because it appeared in multiple European royal families The mutant allele is no longer present in the current British royal family They descend from King Edward VII, Victoria’s son who was not affected Therefore he could not pass on the mutant allele Unit 2: Genetic Linkage Linked genes on the same chromosome Mendel’s second law states that two genes sort independently​during gamete formation This is not always true What if two genes are physically attached (linked genes) on the same chromosome? Example: the human X chromosome in females during prophase I of meiosis I Size: 155 megabases (~155 million bp) Contains ~1100 genes Annotated genes on X chromosome: Dystrophin gene → required for muscle cell development HPRT1 gene → mutations cause severe recurring acute arthritis Colour-blindness gene Hemophilia gene Genes positioned close together on the same chromosome are linked genes Tend to be inherited together Do not segregate independently Example of linked genes: Colour-blindness gene and hemophilia gene (both on X chromosome) Key question: Will linked genes always be inherited together? Breaking linkage through recombination Linked genes are not always inherited together Linkage between them can be broken During prophase I of meiosis, homologous chromosomes: Line up side-by-side Form chiasmata (crossovers) At these crossover points, the linkage between neighboring genes on the chromosome is broken When recombination occurs: Alleles of neighboring linked genes can become separated Linked alleles may be ​inherited independently​in offspring As a result: Some offspring inherit only one of the formerly linked genes Because recombination events disrupted the linkage Recombination frequency & gene distance During recombination, the positions of genes do not change Relative association of alleles changes If linked genes are far apart, crossover events can create recombinant chromatids carrying new allele combinations Example: two genes A and B located on homologous chromosomes One chromosome: A B Other chromosome: a b If a crossover occurs between the two genes: Recombinant gametes produced: Ab aB In addition to parental (non-recombinant) gametes: AB ab If the linked genes are very close together​: No crossover occurs between the genes Any crossover that does occur is outside the region No recombination of alleles is expected between these genes Therefore: Genes closer together → low recombination frequency Genes farther apart → high recombination frequency Recombination frequency is a tool used to determine distance between genes on the same chromosome 11/27/25, 3:07 AM Unit 3: Constructing linkage maps Linkage, recombination, and linkage mapping Genes that are close together​on the same chromosome are typically inherited together Pedigree tracking color-blindness and hemophilia shows that these two traits are linked Exception: an individual in generation IV has only hemophilia His mother was a carrier for both traits Based on linkage, both traits should have been inherited together The fact they were separated indicates a crossover (recombination) occurred between the two genes The frequency of these exceptions provides distance between genes Relative distance between genes allows construction of a linkage map A linkage map shows: Distances between genes Order of genes along the chromosome Based on this pedigree and many others: Color-blindness gene and hemophilia gene are ~12 map units (centimorgans) apart ≈ 12 million base pairs on the X chromosome 11/27/25, 3:07 AM This distance is large enough for crossing over to occur, explaining why the traits occasionally separate High-density linkage maps & SNP markers Linkage maps for human genes are useful But many genes lie millions of base pairs apart Human traits often require observable phenotypes, making classical linkage maps impractical Instead, we use millions of SNPs and other non-coding markers to create high-density linkage maps High-density maps identify loci only a few thousand base pairs apart Even though SNPs are in noncoding regions, they are extremely useful The principle remains the same: Use recombination frequency to determine relative distance between loci (fixed location of a gene) Works for gene ↔ gene, marker ↔ marker, or gene ↔ marker Example: Using markers to locate a disease gene Gene has two alleles: mutant and non-mutant Marker has two alleles: G-C pair and A-T pair Case 1: Marker B (far from the gene) Gene and marker B are far apart → recombination always occurs G-C and A-T are not consistently associated with mutant or non-mutant alleles Offspring show all four allele combinations equally (25% each) Means no association Gene and marker B are unlinked Case 2: Marker A (close to the gene) Gene and marker A are close → recombination is rare Offspring show unequal allele combinations Mutant + G-C = 49% Nonmutant + A-T = 49% These combinations occur much more frequently 11/27/25, 3:07 AM This indicates: Low recombination frequency The disease gene and marker A are linked Distance is small between them Because the positions of markers are known (SNP) from the human genome map The ​approximate location of the disease gene can be identified GWAS (Genome-Wide Association Studies) Pedigree analysis is limited to a few hundred or thousand related individuals With human SNP-linkage maps and fast, inexpensive SNP detection, researchers can study tens of thousands or hundreds of thousands of unrelated individuals A Genome-Wide Association Study (GWAS) looks across the entire SNP-linkage map GWAS searches for an association between a particular phenotype and a mapped SNP Example: An association was found between height and a specific marker allele This identified the HMGA2 gene as contributing to increased height Two “C” alleles → 0.8 cm taller than two “T” alleles Heterozygotes (C/T) → 0.4 cm taller than “T/T” GWAS helps identify genes contributing to various ​human characteristics Used to identify genes linked to diseases such as: Heart disease Cancer Diabetes