Human Genetics 32

Overview of Hardy-Weinberg and Population Dynamics

• Hardy-Weinberg Equilibrium (Chapter 15): Occurs when genetic variation in a population remains constant from one generation to the next in the absence of disturbing factors. This requires five specific assumptions to be met:     * Large population size.     * No mutation.     * No migration (gene flow).     * Random mating.     * No natural selection.

• Microevolution (Chapter 16): Focuses on situations where these equilibrium conditions are not met, leading to shifts in allele frequencies due to migration, mutation, genetic drift, and natural selection.

Genetic Drift and the Founder Effect

• Definition of Genetic Drift: Changes in allele frequency due to sampling errors. It occurs when a small group is sampled from a larger population, failing to represent the entire genetic diversity of the source.

• The Founder Effect: A type of genetic drift that happens when a small group of individuals leaves a main population to establish a new one in a different location.     * Case Study: Variegate Porphyria in South Africa:         * Condition: A skin disorder resulting from a defect in heme production (the iron-binding component in blood cells).         * Origin: Traceable to a single couple from The Netherlands who migrated to South Africa in $1688$.         * Impact: Because this couple carried the allele, they introduced it to the new population. Today, approximately $30,000$ Afrikaners have the disorder due to this single founding event.

• Steel Syndrome in New York City:     * Symptoms: Joint issues and bilateral hip dysplasia (hips not in the correct place), making individuals poor candidates for hip replacements.     * Population: Observed in people of Puerto Rican ancestry, specifically in East Harlem.     * Cause: The population is interbreeding (endogamy) rather than breeding with external populations, causing a specific point mutation to remain prevalent.

Population Bottlenecks

• Definition: A sharp reduction in the size of a population due to environmental events (temperature changes, catastrophic events) or human activities (hunting to near extinction).

• Consequences: Even if the population size rebounds, genetic variability is significantly decreased, leaving the species less able to adapt to future environmental changes.

• Human History Examples:     * Early Human Bottleneck: Genetic evidence shows a period where human genetic diversity was extremely low. Populations that stayed in Africa remain more genetically diverse than those whose ancestors left Africa, as the latter groups represented small, less diverse "bottlenecked" samples.     * Micronesia: A typhoon led to geographic and cultural isolation, resulting in an increased frequency of a specific type of blindness.     * Ashkenazi Jewish Population: This group has undergone multiple bottlenecks throughout history due to massacres (including the Nazi era) and persecution. Combined with mating within the population, this has led to a higher prevalence of specific disease alleles, such as Tay-Sachs disease, compared to the general public.

Mutation as a Source of Genetic Variability

• Nature of Mutations: They are a continual source of genetic variability arising from mistakes made by DNA polymerase during replication.     * Directionality: Mutations are not unidirectional; a wild-type allele $A$ can mutate to $a$, and $a$ can mutate back to $A$.     * Sources of Variation: Point mutations, independent assortment, crossing over, and copy number variable repeats.

• Genetic Load: The collection of recessive deleterious alleles maintained in a population.     * Prevalence: On average, an individual carries at least $20$ recessive alleles for various conditions.     * De Novo Mutations: Each child has, on average, $170$ new mutations not inherited from their parents (occurring in the egg or sperm). Most are "silent" and do not affect phenotype unless influenced by selection or population size.

• Case Study: Phenylketonuria (PKU):     * Mechanism: People with PKU lack the enzyme to break down phenylalanine and aspartame. Aspartame (found in diet sodas) builds up and becomes toxic.     * Origin: The PKU allele originated from a new mutation in Yemen and began spreading globally around $1809$ due to migration.     * Aside on Sweeteners: The speaker notes that Saccharin (pink packet) is so sweet it causes taste receptor neurons to spike so high that the signal is interpreted as bitter. Aspartame (blue) and Splenda (yellow) are less sweet, while Stevia (green) is plant-based.

Natural Selection

• Definition: The process where individuals with traits better suited to their environment are more likely to survive and, crucially, reproduce.

• Reproductive Success: This is the most important factor of natural selection, as it ensures alleles are transmitted to the next generation.

• Selection Types:     * Negative Selection: The removal of deleterious alleles from a population (e.g., an allele causing death before reproductive age).         * Note on Huntington's Disease: While dominant, it is not removed by natural selection because its effects usually appear after the individual has reached reproductive age.     * Positive Selection: The retention of advantageous, highly variable alleles.         * Discovery: Historically, only negative selection was known. In the early $1990s$ (around $1992$), researchers like Austin Hughes at Penn State identified the first examples of positive selection in the antigen-binding sites of antibodies.         * Immune System Examples: HIV and COVID-19 (specifically the spike protein) are under positive selection to escape the human immune system.

Case Studies in Selection and Adaptation

• The Sherpa and High Altitude:     * Sherpas possess mutations in the hypoxia-inducible factor allele $EPAS1$, allowing adaptation to low oxygen.     * They also have specific hemoglobin sequences that bind oxygen more tightly.

• Artificial Selection (Dogs):     * Humans have controlled dog breeding for roughly $30,000$ to $40,000$ years, selecting for mutations like fur type, size (Chihuahuas), and personality.     * Docility and Floppy Ears: The genes for docility and floppy ears are linked in the dog genome (derived from neural crest cell lines). Selecting for "nicer" dogs naturally resulted in dogs with floppy ears.     * Comparison to Cats: Cats have been selectively bred for only about $3,000$ years, which is why they show significantly less phenotypic variability than dogs.

• Antibiotic Resistance:     * Antibiotics kill susceptible bacteria, allowing resistant mutants to flourish.     * Mechanisms of Spread: Resistance can be passed vertically (mutation to daughter cells) or horizontally via conjugation (using transposons to transfer genetic info between bacteria).

Balanced Polymorphism and Heterozygote Advantage

• Definition: A situation where a harmful recessive allele is maintained in a population because the heterozygote (carrier) has a health advantage.

• Sickle Cell Disease:     * $aa$: Individuals have sickle-shaped cells, suffer pain, and have low oxygen transport.     * $AA$: Wild-type individuals are susceptible to the malaria parasite (Plasmodium falciparum), which replicates in red blood cells.     * $Aa$: Heterozygotes have "crystalline" hemoglobin that prevents malaria parasite reproduction but still carries enough oxygen. In malaria-heavy regions (Africa, Central America), this balances the population.

• Cystic Fibrosis (CF):     * Condition: Mutated $CFTR$ protein affecting chloride ion transport.     * Heterozygote Advantage: Discovered in $1998$. Heterozygotes ($Cc$) have fewer chloride ions in their intestines, leading to less water loss during diarrheal diseases (like cholera).     * Demographics: The frequency of the CF allele is higher in Caucasians because it historically protected against death from diarrheal infections.

Eugenics and Bioethics

• Definition: On a societal level, the control of human reproduction to change a population's genetic structure to favor "desirable" traits.

• Types of Eugenics:     * Positive Eugenics: Promoting reproduction among those considered "superior."     * Negative Eugenics: Interfering with the reproduction of those judged "inferior."

• Historical Context:     * In the $1920s$, genetics textbooks often presented eugenics as a positive scientific advancement.     * Nazi Germany: Practiced extreme eugenics by targeting specific populations for elimination.     * United States History:         * In $1906$, a book encouraged selective immigration.         * Carrie Buck (1927): The first person in the US effectively sterilized for having "socially inadequate offspring." The court famously stated, "Three generations of imbeciles are enough."     * International Forced Sterilizations: Cases occurred in Sweden and China (the one-child policy, which significantly skewed the sex ratio toward males).

• Current Implications: Selective sterilization still exists in some US states under strict court orders for severely disabled individuals to simplify care (e.g., preventing puberty).