# Lecture 24: Heredity and Clinical Correlations

## Anatomy and Physiology II

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## Learning Objectives

By the end of this lecture, students will be able to:

1. Define key genetics terminology (gene, allele, genotype, phenotype, homozygous, heterozygous, dominant, recessive)
2. Describe the relationship between DNA, chromosomes, and genes
3. Explain the patterns of inheritance: autosomal dominant, autosomal recessive, X-linked, and codominant/incomplete dominance
4. Use Punnett squares to predict genotypic and phenotypic ratios for single-gene traits
5. Explain the genetic basis of sex determination and sex-linked inheritance
6. Describe polygenic inheritance, multifactorial traits, and the role of environmental factors
7. Identify clinically significant genetic disorders and chromosomal abnormalities

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## Lecture Content

### I. Foundations of Heredity

#### Chromosomes and Genes

Human somatic cells are **diploid (2n = 46)**, containing 22 pairs of autosomes plus 1 pair of sex chromosomes (XX in females, XY in males). Gametes (sperm and oocyte) are **haploid (n = 23)**, carrying one chromosome from each pair. A **gene** is a segment of DNA on a chromosome that codes for a specific protein or functional RNA, and a **locus** is the specific position of a gene on a chromosome.

An **allele** is an alternative form of a gene at a given locus; homologous chromosomes carry alleles for the same genes but may carry different alleles. The **genotype** refers to the genetic makeup of an individual (the alleles present), while the **phenotype** is the observable physical or biochemical expression of the genotype. An individual who is **homozygous** carries two identical alleles (AA or aa), while a **heterozygous** individual carries two different alleles (Aa). A **dominant allele** is expressed in the phenotype when present in one or two copies (represented by uppercase letters), while a **recessive allele** is expressed only when homozygous (represented by lowercase letters). A **carrier** is a heterozygous individual (Aa) who carries one copy of a recessive allele without showing the trait.

### II. Patterns of Inheritance

#### A. Autosomal Dominant Inheritance

In autosomal dominant inheritance, the trait is expressed in heterozygotes (Aa) and homozygous dominant individuals (AA). Only one copy of the dominant allele is needed to express the trait, so affected individuals usually have at least one affected parent. Each child of an affected heterozygous parent has a **50% chance** of inheriting the trait. Examples include Huntington disease, Marfan syndrome, achondroplasia (dwarfism), polycystic kidney disease (autosomal dominant form), and familial hypercholesterolemia.

#### B. Autosomal Recessive Inheritance

In autosomal recessive inheritance, the trait is expressed only in homozygous recessive individuals (aa). Heterozygous carriers (Aa) are phenotypically normal but can pass the allele to offspring. The trait often appears to "skip" generations. When both parents are carriers (Aa x Aa), there is a **25% chance** of an affected child (aa), a **50% chance** of carriers (Aa), and a **25% chance** of homozygous normal individuals (AA). Examples include cystic fibrosis, sickle cell disease, phenylketonuria (PKU), Tay-Sachs disease, albinism, and thalassemia.

#### C. X-Linked (Sex-Linked) Recessive Inheritance

In X-linked recessive inheritance, the gene is located on the X chromosome with no corresponding allele on the Y chromosome. Males (XY) are more commonly affected because they have only one X chromosome, meaning a single recessive allele will be expressed (hemizygous). Females (XX) are usually carriers, with one normal allele masking the recessive one, and are affected only if homozygous recessive. Affected fathers cannot pass the trait to sons (since sons receive the Y from their father), while all daughters of affected fathers become carriers. Carrier mothers have a **50% chance** of affected sons and a **50% chance** of carrier daughters. Examples include hemophilia A and B, Duchenne muscular dystrophy, red-green color blindness, and G6PD deficiency.

#### D. X-Linked Dominant Inheritance

X-linked dominant inheritance is rare. A single copy of the dominant allele on the X chromosome produces the trait. Affected fathers pass the trait to all daughters but no sons. An example is hypophosphatemic rickets (vitamin D-resistant rickets).

#### E. Codominance and Incomplete Dominance

In **codominance**, both alleles are fully expressed in the heterozygote. The classic example is the ABO blood type system, in which the IA and IB alleles are codominant: both A and B antigens are expressed in type AB. In **incomplete dominance**, the heterozygote shows a phenotype intermediate between the two homozygotes. Sickle cell trait (HbAS) provides an example: heterozygotes produce both normal (HbA) and sickle (HbS) hemoglobin, experience mild sickling only under extreme conditions, and gain resistance to malaria.

<image>A multi-panel figure illustrating inheritance patterns. Panel A (Autosomal Recessive — Cystic Fibrosis): A Punnett square showing a cross between two carrier parents (Aa x Aa), with resulting genotypic ratios (1 AA : 2 Aa : 1 aa) and phenotypic ratios (3 unaffected : 1 affected). A pedigree diagram below shows the characteristic pattern with unaffected parents producing affected children, the trait appearing to skip generations. Panel B (X-Linked Recessive — Hemophilia): A Punnett square showing a carrier mother (X^H X^h) crossed with an unaffected father (X^H Y), producing daughters (50% carrier, 50% normal) and sons (50% affected, 50% normal). A pedigree diagram shows the characteristic pattern of affected males, carrier females (indicated by half-filled circles), and the absence of father-to-son transmission. Panel C (Codominance — ABO Blood Types): A diagram showing the three alleles (I^A, I^B, i), the six possible genotypes, and the four phenotypes (Type A, B, AB, O). A Punnett square illustrates a cross between Type A (I^A i) and Type B (I^B i) parents showing the possible offspring blood types.</image>

### III. Sex Determination and Sex-Linked Traits

Sex is determined at fertilization by the sex chromosomes. The oocyte always contributes an X chromosome, while the sperm contributes either an X (producing an XX female) or Y (producing an XY male). The **SRY gene** (sex-determining region of the Y chromosome) encodes a transcription factor that triggers male gonadal development (testes differentiation) at approximately week 7 of embryonic development. Without SRY, the default developmental pathway is female (ovaries develop).

The **Y chromosome** is small and contains relatively few genes (SRY and genes for spermatogenesis), while the **X chromosome** is large and contains approximately 800 genes involved in many non-reproductive functions. **X-inactivation (the Lyon hypothesis)** explains that in females, one X chromosome in each cell is randomly inactivated during early embryonic development, forming a **Barr body** (condensed, inactive X). As a result, females are genetic mosaics for X-linked genes. This phenomenon produces the calico coat coloring in cats and explains manifesting carriers of X-linked disorders.

### IV. Polygenic and Multifactorial Inheritance

#### Polygenic Inheritance

Some traits are determined by the combined effects of two or more genes at different loci, a pattern called polygenic inheritance. Such traits produce a **continuous range of phenotypes** following a bell-shaped distribution rather than discrete categories. Examples include skin color (involving at least 3-6 genes), height, eye color, and intelligence. Predicting outcomes for polygenic traits using simple Punnett squares is not practical.

#### Multifactorial Inheritance

Most common human diseases follow multifactorial patterns, in which traits are influenced by both **genetic factors** (often polygenic) and **environmental factors**. Examples include hypertension, type 2 diabetes mellitus, coronary artery disease, obesity, cancer, schizophrenia, cleft lip and palate, and neural tube defects. Disease expression requires genetic predisposition combined with environmental triggers such as diet, lifestyle, or toxin exposure. Concordance studies in twins help researchers distinguish genetic from environmental contributions to disease.

### V. Chromosomal Abnormalities

#### Numerical Abnormalities (Aneuploidy)

Numerical chromosomal abnormalities result from **nondisjunction**, the failure of chromosomes to separate properly during meiosis. **Trisomy** (2n + 1 = 47) produces an extra copy of one chromosome. **Trisomy 21 (Down syndrome)** is the most common viable trisomy, characterized by intellectual disability, characteristic facial features, congenital heart defects, and increased Alzheimer risk, with incidence increasing with maternal age. Trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome) are both severe, with most affected individuals dying within the first year of life. **Monosomy** (2n - 1 = 45) involves loss of one chromosome. **Turner syndrome (45,X)** is the only viable monosomy, presenting with female phenotype, short stature, webbed neck, shield chest, streak gonads, infertility, and cardiac defects.

Sex chromosome aneuploidies include **Klinefelter syndrome (47,XXY)**, presenting with male phenotype, tall stature, small testes, gynecomastia, infertility, and mild intellectual disability; **47,XYY** (tall males with typically normal fertility and development); and **47,XXX (Triple X)** (usually clinically normal with possible mild learning difficulties).

#### Structural Abnormalities

Structural chromosomal abnormalities take several forms. **Deletion** involves loss of a chromosome segment, as in Cri-du-chat syndrome (5p deletion). **Duplication** involves repetition of a chromosome segment. **Translocation** involves transfer of a segment between non-homologous chromosomes; Robertsonian translocation is a common cause of familial Down syndrome involving translocation between chromosome 21 and another acrocentric chromosome. **Inversion** involves reversal of a chromosome segment.

### VI. Clinically Significant Genetic Disorders — Summary

| Disorder | Inheritance | Gene/Defect | Key Features |
|---|---|---|---|
| Cystic fibrosis | Autosomal recessive | CFTR (Cl- channel) | Thick mucus in lungs, pancreatic insufficiency, salty sweat |
| Sickle cell disease | Autosomal recessive (codominant) | Beta-globin (HbS) | Sickle-shaped RBCs, vaso-occlusive crises, hemolytic anemia |
| Phenylketonuria (PKU) | Autosomal recessive | Phenylalanine hydroxylase | Intellectual disability if untreated; newborn screening |
| Huntington disease | Autosomal dominant | Huntingtin (CAG repeat expansion) | Chorea, psychiatric symptoms, dementia; onset ~30–50 years |
| Marfan syndrome | Autosomal dominant | Fibrillin-1 | Tall stature, long limbs, aortic root dilation, lens dislocation |
| Hemophilia A | X-linked recessive | Factor VIII | Prolonged bleeding, hemarthrosis; predominantly males |
| Duchenne muscular dystrophy | X-linked recessive | Dystrophin | Progressive muscle weakness; onset ~2–5 years; wheelchair by teens |
| Down syndrome | Trisomy 21 | Extra chromosome 21 | Intellectual disability, characteristic facies, heart defects |

### VII. Genetic Screening and Counseling

**Prenatal screening** employs several approaches. Maternal serum markers (alpha-fetoprotein, hCG, estriol, inhibin A) form the quad screen. **Cell-free fetal DNA (cfDNA)** enables non-invasive prenatal testing (NIPT) from maternal blood, screening for common trisomies. **Ultrasound** can measure nuchal translucency (increased in Down syndrome). **Amniocentesis** (performed at approximately weeks 15-18) samples amniotic fluid for fetal cells to allow karyotyping and genetic testing. **Chorionic villus sampling (CVS)** (performed at approximately weeks 10-12) samples placental tissue for earlier karyotyping.

**Newborn screening** tests for conditions including PKU, congenital hypothyroidism, sickle cell disease, and cystic fibrosis, with specific panels varying by jurisdiction. **Genetic counseling** involves assessment of risk, education about inheritance patterns, and discussion of testing options and implications.

<image>A two-panel figure on chromosomal abnormalities and karyotyping. Panel A: A normal human karyotype (46,XY) showing all 22 pairs of autosomes arranged by size and banding pattern plus the sex chromosomes, with group labels (A through G). Alongside, an abnormal karyotype showing trisomy 21 (47,XY,+21) with three copies of chromosome 21 circled and labeled. Panel B: A diagram illustrating nondisjunction during meiosis I — homologous chromosomes failing to separate, resulting in one gamete with an extra chromosome (n+1) and one gamete missing a chromosome (n-1). When the n+1 gamete is fertilized by a normal gamete, the resulting zygote is trisomic (2n+1). A second diagram shows nondisjunction during meiosis II with sister chromatids failing to separate. Clinical photographs or schematic representations of key features of Down syndrome, Turner syndrome, and Klinefelter syndrome are shown alongside their respective karyotypes.</image>

### VIII. Clinical Correlations

**Pharmacogenomics** recognizes that genetic variations affect drug metabolism. For example, CYP450 polymorphisms influence warfarin dosing and codeine metabolism. **Epigenetics** involves heritable changes in gene expression without altering the DNA sequence (through DNA methylation and histone modification); these changes are influenced by the environment and may explain some multifactorial disease patterns. **Genetic imprinting** means that expression of certain genes depends on the parent of origin. Prader-Willi syndrome and Angelman syndrome involve the same chromosomal region (15q) but differ depending on which parent's copy is affected. **Mitochondrial inheritance** follows exclusively maternal transmission because mitochondrial DNA is inherited only from the mother. Mutations cause mitochondrial diseases such as Leber hereditary optic neuropathy and MELAS.

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