Genetics Lecture Notes - Fall 2025

Topics Covered:
- What is a gene
- Definition
- Organization of the human genome
- Genetic diversity
- Mendelian gene inheritance
- Monogenetic human disorders in nutrition and metabolism
- Absorption disorders
- Cystic fibrosis
- Hereditary hemochromatosis
- Metabolic synthesis/processing disorders
- Phenylketonuria
- Energy generation disorders
- Mitochondrial defects

Main Focus:
- Non-Mendelian inheritance
- Methods to study genetic factors in diseases
- Genome-wide association studies (GWAS)
- The genetic basis of obesity
- Nutritional genomics

Characteristics:
- Most physical characteristics and human diseases are polygenic, determined by a combination of multiple genes.
- Environmental factors also influence the phenotype alongside genetic factors.

Defined as traits where the phenotype results from interactions among multiple genes.
Example: Eye color is determined by at least 8 genes influencing a spectrum of colors.
Complexity in Inheritance:
- Increased number of genes affecting the phenotype leads to more complex inheritance patterns.

Family History:
- Collect information on family members with and without the disease to identify Mendelian inheritance patterns.
- Tools used: Genetic sequencing of affected and unaffected family members to find mutations.
- In polygenic diseases, first-degree relatives may share the disease without classic Mendelian patterns.
- Variability in genetic composition among families affects inheritance patterns.
Twin Studies:
- Identical Twins (Monozygotic): 100% genetic identity since they originate from one embryo.
- Fraternal Twins (Dizygotic): 50% genetic identity from two separate fertilizations.
- Observation: If a disease occurs more in monozygotic twins compared to dizygotic twins, genetic factors likely contribute to the disease.
Adoption Studies:
- Comparative analysis between adopted individuals and their adoptive and biological families.
- If adopted individuals show traits similar to biological parents, this signals a genetic component.
Genome-Wide Association Studies (GWAS):
- Observational case-control studies to find significant associations between genetic mutations and polygenic diseases.
- Process: Collect genetic data from groups with and without diseases and identify mutations prevalent in the disease group compared to controls.

Whole Genome Sequencing:
- Provides a complete mutation profile but is expensive and often impractical for large studies.
Single Nucleotide Polymorphism (SNP) Database:
- Utilizes existing databases for known mutations, focusing on SNPs as they are faster and cheaper to analyze than whole genome sequencing.
- Example of SNP: 5’-ATCTCAGA (SNP-related mutations examined).
- Advantages: Greater allele coverage increases the likelihood of finding disease-associated SNPs.

Utility of SNPs:
1. Ideal cases where SNPs are direct mutations responsible for diseases are rare; most SNPs lie in non-coding regions.
2. SNPs serve as genetic ‘bookmarks’ to indicate regions of chromosomes potentially containing actual disease-related genes or other impactful mutations.
The abundance of SNPs directly relates to the chance of identifying disease associations.
The Human Genome Project has enhanced SNP discovery capabilities significantly.

Sample Sizes in GWAS: Studies can involve millions of individuals, leading to identification of numerous genetic variants impacting phenotypes.
For instance, discovered over 12,111 genetic factors associated with height.

Prevalence: Obesity rates are rising globally, attributed not only to environmental but also strong genetic factors.
Reference: Loos, R.J.F., Yeo, G.S.H. - The genetics of obesity: from discovery to biology (Nat Rev Genet).

A meta-analysis of 88 twin studies indicates significant genetic components affecting Body Mass Index (BMI).
Family studies corroborate findings from twin studies with heritability indices ranging from 0 (no genetic influence) to 1 (complete genetic determination).

Monogenic Obesity:
- Caused by mutations in single genes and is relatively rare but has substantial effects.
- Example: Leptin-related mutations leading to obesity were first studied in mice (1950).
Polygenic Obesity:
- More common and complex, affected by many variants with smaller individual impacts.
- GWAS Outcome: Identified over 1,100 loci associated with different obesity-related traits.
- Despite substantial findings, only 3-5% of obesity heritability is explained by current GWAS data.

Definitions:
- Nutrigenetics: Focuses on how genotype affects the metabolism of food, dietary needs, and tolerances.
- Nutrigenomics: Examines how nutrient consumption affects gene expression.
Examples of Nutrigenetic Disorders:
- Hereditary hemochromatosis, Phenylketonuria, Lactose intolerance, Alcohol flushing syndrome.

Influence of bioactive food components on gene expression can occur at any point in gene expression processes: transcription, translation, and post-translational modifications.
Example Involving SAM: Folate helps synthesize S-Adenosyl-Methionine (SAM) which is critical for DNA methylation - a key process for gene expression regulation.

Overview: Precision nutrition aims to provide customized dietary recommendations tailored to individual genetics.
Supported by the US National Institutes of Health (NIH), the Nutrition for Precision Health program seeks to integrate diverse data sources for better understanding dietary habits.
Quote from Dr. Holly Nicastro: Precision nutrition is an actionable approach to dietary health that is personalized at the level of each individual.
NIH commitment: Dedicated $170 million for advancing precision nutrition research.

All discussed factors (genetic, metabolic, and environmental) should be considered when translating nutritional research into public health and policy.

Articles and studies mentioned throughout the notes:
- Loos, R.J.F., Yeo, G.S.H. - The genetics of obesity: from discovery to biology.
- GWAS related studies and methodologies.
- Nutritional genomics impact studies and implications.