The document discusses the history and concepts of heredity and genetics including: 1) Early ideas from Aristotle and others about inheritance being determined by semen and eggs. 2) Mendel's laws of inheritance including uniformity, segregation, and independent assortment. 3) The connection between chromosomes and heredity including Sutton and Boveri's chromosome theory. 4) DNA being identified as the basis of inheritance through unraveling the genetic code.

1. The concept of heredity
Inheritance of single gene disorders
Polygenic and multifactorial inheritance
Molecular pathology in genetic diseases deviating from classic inheritance
Functional importance of epigenetic mechanisms in genome, and the role in development and
disease etiopathogenesis

2. Aristotle and Hippocrates concluded:
important human characteristics were determined
by semen, using menstrual blood as a culture
medium and the uterus as an incubator.
Leeuwenhoek and de Graaf recognized the
existence of sperm and ova, thus explaining how
the female could also transmit characteristics to
her offspring.
Pierre de Maupertuis, a French naturalist, studied
hereditary traits such as extra digits (polydactyly)
and lack of pigmentation (albinism), and showed
from pedigree studies that these two conditions
were inherited in different ways.
Joseph Adams (1756–1818), a British doctor, also
recognized that different mechanisms of
inheritance existed.

3. The Law of Uniformity
When two homozygotes with different alleles are crossed, all of the offspring in the F1 generation are identical and
heterozygous. In other words, the characteristics do not blend, as had been believed previously, and can reappear in
later generations.
The Law of Segregation
Each person possesses two genes for a particular characteristic, only one of which can be transmitted at any one
time. Rare exceptions to this rule can occur when two allelic genes fail to separate because of chromosome non-
disjunction at the first meiotic division.
The Law of Independent Assortment
Members of different gene pairs segregate to offspring independently of one another. In reality, this is not always
true, as genes that are close together on the same chromosomeanother tend to be inherited together, because they
are ‘linked’ (p. 136). There are a number of other ways by which the laws of mendelian inheritance are breached but,
overall, they remain foundational to our understanding of the science.
Gregor Mendel (1822-1884)

4. Human mitotic figures were observed from the late
1880s, and it was in 1902 that Walter Sutton, an
American medical student, and Theodour Boveri, a
German biologist, independently proposed that
chromosomes could be the bearers of heredity
(chromosome theory).
Thomas Morgan transformed Sutton’s chromosome
theory into the theory of the gene, and Alfons
Janssens observed the formation of chiasmata
between homologous chromosomes at meiosis.
The connection between mendelian inheritance and
chromosomes.
DNA as the Basis of Inheritance
Unraveling the genetic code

5. Patterns of Inheritance
• Chromosomal
• Single gene (Mendelian)
• Multifactorial
• Non-Mendelian
– Mitochondrial inheritance
– Imprinting
– Uniparental disomy
• Somatic cell genetic disorders

6. Chromosome Abnormalities
• Numerical
– Aneuploidy
– Polyploidy
• Structural
– Translocation
– Deletion
– Inversion
– Duplication
– Ring
– Isochromosome

7. Single Gene Disorders
• Autosomal dominant
• Autosomal recessive
• X-linked dominant
• X-linked recessive
• Y-linked ?

8. Multifactorial Disorders
both genetic and environmental factors are
involved in causing the disorder
• congenital malformations
• common (complex) disorders

9. mitochondrial disorders
(maternal inheritance)

10. somatic cell
genetic disorders

11. Number of Entries
(Updated February 17th, 2017)
Autosomal X-Linked Y-Linked
Mitochondria
l
Total
* Gene description 15347 734 49 37 16167
+ Gene and phenotype, combined 39 0 0 0 39
# Phenotype description,
molecular basis known 5257 339 5 33 5634
% Phenotype description or locus,
molecular basis unknown 1434 119 4 0 1557
Other, mainly phenotypes with
suspected mendelian basis 1642 105 3 0 1750
Total 23719 1297 61 70 25147
OMIM* Statistics
*: Online Mendelian Inheritance in Man
https://www.omim.org/statistics/entry
Updated September 13th, 2019

12. Frequency of Different Types of Genetic Disease
Type
Incidence at Birth
(per 1000)
Prevalence at Age
25 Years (per
1000)
Population
Prevalence (per
1000)
Disorders due to
genome and
chromosome
mutations
6 1.8 3.8
Disorders due to
single-gene mutations
10 3.6 20
Disorders with
multifactorial
inheritance
50 50 600

13. • 50% of all conceptions are lost before
implantation or shortly afterwards
(before the woman realizes she is pregnant)
• 15% of recognized pregnancies end in
spontaneous miscarriage before 12 weeks’
gestation
Chromosomal abnormalities are found in about
50% of all spontaneous abortions
This rises to 60% if a gross structural abnormality
is present

14. Incidence of Chromosome Abnormalities at
Different Stages of Fetal or Postnatal Life
Abnormal Karyotype
First-Trimester
Abortuses
Fetuses of Mothers > 35
Years*
Live
Births
Total incidence 1/2 1/50 1/160
Percentage of
abnormalities
Numerical
abnormalities
96% 85% 60%
Structural
abnormalities
Balanced 0% 10% 30%
Unbalanced 4% 5% 10%

15. • 25-30% of all perinatal deaths
(after 28 weeks’ gestation plus the first week of life)
occur as a result of structural anomaly
• and genetic factors are responsible for
about 80% of these cases

16. 2-3 % of all newborns have at least one major malformation
(adverse outcome on the function or social acceptability of the
individual)
10 % of all newborns have at least one minor malformation
if someone has 2 or more minor malformation, there is a risk of
having major malformation with a probability of 10-20 %
25 % death in early infancy
25 % mental and physical problems
of all newborns;
0.5 % chromosomal anomaly
1 % single gene disorder

17. Causes of congenital malformations

18. Adulthood:
common diseases

19. genetic basis of common disorders:
genetic susceptibility

20. Risk Ratios λr for Siblings of Probands with Diseases with
Familial Aggregation and Complex Inheritance
Disease Relationship λr
Schizophrenia Siblings 12
Autism Siblings 150
Manic-depressive (bipolar) disorder Siblings 7
Type 1 diabetes mellitus Siblings 35
Crohn's disease Siblings 25
Multiple sclerosis Siblings 24

21. Empirical Risks for Counseling in Type 1 Diabetes
Relationship to Affected
Individual Risk for Development of Type 1 Diabetes
MZ twin 40%
Sibling 7%
Sibling with no DR
haplotypes in common
1%
Sibling with 1 DR
haplotype in common
5%
Sibling with 2 DR
haplotypes in common
17% (20%-25% if shared haplotype is DR3/DR4)
Child 4%
Child of affected
mother
3%
Child of affected father 5%

23. Disease Race Frequency
Porphyria
variegata
South african
(white)
3.0
Caucasians (general) 0.01
Cystic fibrosis N. Europeans 0.4-0.5
Afro-americans,
orientals
0.01

26. Disease Frequency
per 10000
Unimpaired
life
İmpaired
life
Lost life
years
Familial
hypercholesterolemia
20 55 10 5
Congenital deafness 1 0 70 0
Cystic fibrosis
(untreated)
5 2 8 60
Muscular dystrophy
(X-linked)
2 4 16 50