Materials for practical class 5

Variation in human beings. Methods of research of human heredity. Human hereditary diseases.


I. Variation in human beings.

1.     Modification (phenotypic) variation (environmental influences, adaptive character of modification, phenocopies).

2.     Combinatorial variation a basis of phenotypic and genotypic variety of persons in Human’s population.

3.     Mutation and its types.

4.     Genomic mutation (chromosome mutation): 1) polyploidy; 2) aneuploidy.

5.     Chromosomal aberrations: 1) deletion; 2) duplication; 3) inversion; 4) translocation.

6.     Gene mutations: 1) deletion; 2) duplication; 3) inversion; 4) insertion.

7.     Germinal and somatic mutations.

8.     Origin of mutations (physical, chemical, biological mutagens).

Variationis deviation in characters in an individual from those typical of the species to which it belongs. Variation of organisms is subdivided into: 1) non-hereditary (phenotypic or modification) and 2) hereditary (genetic variation).

         Phenotypic (modification) variation—changes of phenotype without changes of the genotype, these changes are adaptive reactions to external stimuli and they do not inherit.

         Hereditary (genetic variation) is subdivided into: 1) combinatorial variation and 2) mutation.

         Combinatorial variationis formation of new combinations of genotypes by shuffling of parental genes. New genotypes arise in 3 ways:

1)    recombination of linked genes in chromosomes by crossing over in the prophase of meiosis;

2)    independent assortment of chromosomes during meiosis;

3)    random chromosomes combination during fertilization.


As a result of combinatorial variation is diviation in characters of the offspring from those of its parents.

          Mutation—a permanent transmissible change in the genetic material (modification in chromosomes and genes). There are 3 main types of mutations:

1)      chromosome mutations (genomic mutation)—are changes in number of chromosomes in karyotype;

2)      chromosome aberrations—are changes in structure of chromosomes;

3)      gene (point) mutations—are changes in structure of the nucleotides.

        Сhromosome mutations are  subdivided into:

1) polyploidythe state of having more than diploid set of chromosomes (3n—triploid, 4n—tetraploid, 5n—pentaploid, 6n—hexaploid);

2) aneuploidyany deviation of the diploid number of chromosomes, an individual or cell having a missing (2n-1) or extra (2n+1) chromosomes.



        Chromosomal aberrations are caused changes in structure of chromosomes. They occur in 4 ways:

1) deletion (a segment of chromosome separates and is lost);

2) duplication (a segment of a chromosome joins a part of homologous chromosome);

 3) inversion (a segment of a chromosome breaks off and rotates through 180º and rejoining the chromosome);

4)      translocation (a segment of a chromosome breaks off and joins a non-homologous chromosome).



        Gene mutation is the result of a change in the nucleotide sequence of the DNA molecule. As a result is a change in the amino acid sequence of the polypeptide chain.

There are 4 forms of gene mutation:

1)    deletion;

2)      duplication;

3)      inversion;

4)     insertion.


Mutation may be germinal and somatic.

        Germinal mutation—a mutations in germ cells (gametes) can be transmitted to offspring.

Somatic mutation—a mutation in a somatic cells, these mutations will not be transmitted to offspring if sexual reproduction takes place.

        Mutant—an organism that has genetic mutation.


 Mutagen—a chemical or physical agent that induces or increases genetic mutations.

        The same allele combination can produce different degrees of the phenotype in different individuals. Penentrance is a percent of individuals affected. Example. Polydactyly, having extra fingers or toes, is incompletely penentrant. Cats who inherit the dominant polydactyly allele have more than 4 toes on at least one paw, yet others who are known to have the allele (because they have an affected parent and offspring) have the normal number of toes. The penetrance of a gene is described numerically. If 80 of 100 cats who inherit the dominant polydactyly allele have extra digits, the allele is 80 % penentrant.

A phenotype is variably expressive if the symptoms vary in intensity in different individuals. Expressivity is an intensity of symptoms. Example. One cat with polydactyly might have two extra digit on two paws; a third cat might have just one extra toe. Penentrance refers to the all-or-none expression of a genotype; expressivity refers to the severity of a phenotype.

Some gene expressions are exquisitely sensitive the environment. Temperature influences gene expression in some familiar animals - Siamese cats and Himalayan rabbits has dark ears, noses, feet, and tails because these anatomical extremities tend to be colder than the animal's abdomens. Heat destroys pigment molecules that provide coat color.

II. Methods of research of human heredity

1.   Human organism as a specific object of the genetic analysis.

2.   Methods of human genetics: Genealogy method (Pedigree Analysis), Twin method (study of Twins).

3.   Rules of Genealogy.

4.   Types of inheritance: autosomal-dominant, autosomal-recessive, X-linked recessive, X-linked dominant, Y-linked.

5.   Analysis of the pedigree: determination of type of inheritance, proband’s genotype, probability of   the sick children birth in the proband’s family.


      The principles of genetics we have studied are not applicable just to peas and fruit flies. Human organism is a specific object of the genetic analysis. Breeding experiments don’t carry out for human beings. Human families are small, and 20 to 30 years or more elapse between generations. Human  karyotype is difficult (46 chromosomes; 23 linkage groups). The human population is very diverse and individuals are heterozygous for many genes.

       Main methods of human genetics are: Genealogy method (Pedigree Analysis), study of Twins, Dermatoglyphics, Cytogenetical method (Chromosomes Analysis), DNA Analysis.

          Genealogy method  (Pedigree Analysis).  Pedigree – a diagram of an individual’s ancestors, used by the human genetics for the analysis of inheritance. Analysis of pedigrees complements segregation analysis in proband and is suited to answer some questions about which single proband is uninformative. It consists largely in drawing family trees and attempting to establish the genotype of each person on the basis of his relationship to others.

Symbols used in pedigree diagrams.


Types of inheritance:

    Autosomal-Dominant inheritance occurs when:

1)  a trait can effect both sexes (female  and male  can be ill);

2)      the  trait  is inherited vertically in the pedigree (it affects every generation);

3)      one or both parents of ill child are ill.


Pedigree 1Autosomal-Recessive inheritance:

1)  a trait can effect both sexes (female  and male  can be ill);

2)      the trait is inherited horizontally  in the pedigree (it does not affect every generation);

3)      parents of ill child can be healthy in the phenotype, but they are heterozygous and carriers of mutant  gene (individuals who have affected children must both be carriers);

4)  probability of the sick children birth  is higher in family marriages (members are closely related).

    X-Linked Recessive inheritance:

1) a trait affects mostly males;

2)     the trait does not pass from  father to  son.

    X-Linked Dominant inheritance:

1)  a trait  affects mostly females;

2)    if the affected female is heterozygous, she will pass Pedigree 5the trait to a half  of her offspring (male and female);

3)    an affected male passes the trait to his daughters.










 Y-Linked inheritance: 1) a trait affects only males; 2) father passes a trait  to all sons.

          Twin method. There are two kinds of twins, the so-called identical (monozygotic) and fraternal (dizygotic) twins. Monozygotic (MZ) twins arise from a single zygote that is divided into two separate embryos very early in gestation. Because only one zygote is involved, the twins are genetically identical. Dizygotic (DZ) twins arise from two zygotes that are produced by fertilization of two separate ova (dioval twins). Thus they have the same genetic relationship as ordinary sibs. They may be either of one sex  (two boys or two girls) or different sexes (a boy and a girl). Monozygotic twins must be of one sex. Other traits include the blood groups, plasma protein types, and salivary secretion of antigens. A difference of any system is adequate evidence to classify a pair of twins as DZ. More complex traits may also be considered: finger and palm prints, hair colour, eye colour, and morphology of skeletal and other tissues, such as teeth, ears, and nostrils.  If trait is in both twins, they are concordance. Concordance is percent of similar to learning trait. Discordance is absence a trait in one of twin.





Blood groups (ABO)



Colour of eyes



Finger and palm prints






If a condition due to a genetic component concordance rates are different for both types of twins. For example, blood groups, color of eyes. If a condition has no genetic component concordance rates are similar for both types of twins. For example, measles.


  III. Human hereditary diseases.

1. Autosomal chromosome abnormalities.

1.1. Numeral changes (aneuploidy) in autosomes.

1.2. Structural changes of chromosomes.

2. Numeral changes (aneuploidy) in sex chromosomes.

3. Chromosomal mosaicism


There are 4 main types of the genetic disorders:

1.  Abnormalities (Aneuploidy) of autosomes: Down syndrome, Patau syndrome, Edwards syndrome.

2.  Abnormalities (Aneuploidy) of sex chromosomes: Turner syndrome, the triplo-X syndrome, Klinefelter’s syndrome, the XYY syndrome.

3.  Abnormalities (chromosome aberrations) of autosomes: the cri-du-chat syndrome (5p-syndrome).

4.   Gene disorders (metabolic disorders or molecular pathology): phenylketonuria, albinism, sickle-cell anaemia, Tay-Sach’s disease, haemophilia, red-green colour blindness.


Nondisjunction. A common cause of changes in chromosome number.

       Abnormalities  of autosomes.

       1. Down Syndrome. The karyotype formula is 47, XX, 21+ or 47, XY, 21+. The frequency of births is 1/700.

Phenotypic effects of trisomy 21. Down syndrome is characterized by a small skull, round face and a long protruding tongue, short, flat-bridge nose, a mongolian type of eyelid fold (epicanthal fold), short neck, short phalanges (fingers), flat hands, unusual finger and palm prints (dermal rings), indcluding transverse palm crease, triradius near center (angle atd is equal to 80 degree). The patients with Down syndrome have mental retardation, little intelligence, abnormalities of heart.


 Etiology of Down syndrome. The cause of Down syndrome is that during anaphase of meiosis chromosomes of 21 pair didn’t disjoin and move to opposite poles of the cell. As result gametes (eggs or sperm cells) have 22 chromosomes (-21th) or 24 chromosomes (+21th). When normal gamete with 23 chromosomes fuses with gamete with 24 (+21th) chromosomes, the resulting zygote will be 47,+21 chromosomes and will develop into a Down syndrome (trisomy 21).

  The incidence of nondisjunction rises in the ovaries of aged women. The women above 40 years of age are more likely to produce children having Down’s syndrome. Approximately 1 in every 50 birth is a child with Down syndrome. Reproduction in Down's syndrome should be possible. Meiotic studies in Down syndrome have not been possible in males, but ones have been possible in females with normal ovary.

    May be translocation type of Down syndrome. The karyotype formula is 46,t(15q21q). The diploid number of chromosomes is normal, but the morphology is not. The effects are produced by the translocation of an extra G21 chromosome onto a larger chromosome, usually D15. A translocation of 21 chromosome causes about 6% of Down’s syndrome cases. No clinical distinction has been made between the two types of Down syndrome. A difference between the two types of Down’s syndrome is the absence of a maternal age effect in translocation type.


Table 1: Approximate risks of chromosomal changes associated with maternal age

Maternal age at delivery

* Chance of having a live-born baby with a Down syndrome

** Chance of having a live-born baby with a chromosomal abnormality

20-24 years

1 in 1474

1 in 506

25 years

1 in 1350

1 in 476

26 years

1 in 1290

1 in 476

27 years

1 in 1210

1 in 455

28 years

1 in 1120

1 in 435

29 years

1 in 1020

1 in 417

30 years

1 in 909 ***

1 in 385

31 years

1 in 900***

1 in 385

32 years

1 in 750***

1 in 323

33 years

1 in 625***

1 in 286

34 years

1 in 500

1 in 244

35 years

1 in 384

1 in 179

36 years

1 in 307

1 in 149

37 years

1 in 242

1 in 124

38 years

1 in 189

1 in 105

39 years

1 in 146

1 in 81

40 years

1 in 112

1 in 64

41 years

1 in 85

1 in 49

42 years

1 in 65

1 in 39

43 years

1 in 49

1 in 31

44 years

1 in 37

1 in 24

45 years

1 in 28

1 in 19



2. Trisomy 13 (Patau syndrome). The karyotype formula is 47, XX, 13+ or 47, XY, 13+. The frequency of births is 1/15.000 .

Phenotypic effects of trisomy13.  Patau syndrome is characterized by a various eye defects (including anophthalmia), cleft palate and cleft lip, polydactyly, micrognathia (micromandibula or micromaxilla), low-set, malformed ears and abnormalities of the heart, viscera and genitalia. Dermatoglyphic features include an in­creased frequency of digital arches, a distal axial triradius (angle atd is equal to 108°), and frequently simian flexion creases of the palm. Survival is very limited, approximately 50% die by one month of age.


Etiology of Patau syndrome. The cause of Patau syndrome is that during anaphase of meiosis chromosomes of 13 pair didn’t disjoin and move to opposite poles of the cell. And as result gametes (eggs or sperm cells) have 22 chromosomes (-13th) or 24 chromosomes (+13th). When normal gamete with 23 chromosomes fuses with gamete with 24 (+13th) chromosomes, the resulting zygote will be 47,+13 and will develop into a Patau syndrome (trisomy 13). As with trisomy 21, the risk is higher for older mothers.

3. Trisomy 18 (Edwards syndrome). The karyotype formula is 47, XX, 18+ or 47, XY, 18+. The frequency of births is 1/5.000 .

 Phenotypic effects of trisomy18. Edwards syndrome characterized by mental retardation, scaphocephaly (a condition in which the skull is abnormally long and narrow), hyper-tonicity, low-set, malformed ears, micrognathia, blepharoptosis (drooping of paralitic  upper eyelid), short digits and rocker-bottom feet,  congenital heart defects and other deformaties. Most have arches on six or more fingers, and there is often a single flexion crease on one or more fingers. Fifty percent of the patients die by two months of age, and only a few have been known to survive beyond several years of age. 


Etiology of Edwards syndrome. The cause of Edwards syndrome is that during meiosis in anaphase chromosomes of 18 pair didn’t disjoin and move to opposite poles of the cell. And as result gametes (eggs or sperm cells) have 22 chromosomes (-18th) or 24 chromosomes (+18th). When normal gamete with 23 chromosomes fuses with gamete with 24 (+18) chromosomes, the resulting zygote will be 47,+18  and will develop into a Edwards syndrome (trisomy 18). Older mothers have an increased risk of trisomy 18 offspring.

        4. The cri-du-chat syndrome. The karyotype formula is 46, XX, 5p- or 46, XY, 5p-. Such patients have a small head, low-set malformed ears, abnormalities of the heart and visceral, are mentally retarded. Abnormal development of the glottis and larynx results in the most characteristic symptom – the infant’s cry resembles that of a cat.

         Numeral Abnormalities (Aneuploidy) of Sex chromosome.

              1. Turner syndrome. The karyotype formula is 45, XO, where O indicates absence of the other member of the sex chromosome pair. The frequency of births is 1/2.000.

Phenotypic effects of Turner’s syndrome. Turner syndrome is characterized by a  female phenotype, but ovaries are not properly developed. Individuals with this condition are characterized by short stat­ure, pronounced webbing of the neck, low posterior hair line, infantile genitalia, and lack of de­velopment of secondary sexual characteristics, their mental development is usually within the normal.

Etiology of Turner syndrome. The cause of Turner syndrome is that during meiosis in anaphase sex chromosomes didn’t disjoin and move to opposite poles of the cell. And as result eggs have 22 chromosomes (O) or 24 chromosomes (XX) and sperms have 22 (0) or 24(XX) or 24(XY) chromosomes.   When normal X-sperm fuses with abnormal O-egg or normal X-egg fuses with abnormal O-sperm,  the resulting zygote will be 45,XO and starts out with monosomy X.


Patients with Turner syndrome have negative sex chromatin (Barr body or X-body is not present).   

2.   The triplo-X syndrome. The karyotype formula is 47, XXX. The frequency of births is 1/700.

Etiology of the triplo-X syndrome. The cause of triplo-X syndrome is nondisjuction of sex-chromosome during oogenesis or spermatogenesis, producing two types of egg, XX or O, or three types of sperms: XX, XY and O (O is absence of X or Y chromosomes). Fertilization of an abnormal gamete (XX)  by a normal gamete (X) results in the triplo-X syndrome. 

Phenotypic effects of the triplo-X syndrome. Some females show abnormal sexual development (menstrual irregularity), tall and thin. May be normal fertility and intelligence.

The number of Barr body is equal to two.

          3. Klinefelter syndrome. The karyotype formula is 47,XXY. The frequency of births is 1/2.000.

Phenotypic effects of Klinefelter syndrome. Klinefelter’s syndrome is characterized by male phenotype, small testes, azoospermia (absence of spermatozoa in the semen and infertility). Patients tend to be tall, with long legs, and about half have gynecomastia (excessive growth of the male mamary glangs and breast swelling). The majority of patients are of diminished intelligence, and many are placed in institutions for the mentally defective.


Etiology of Klinefelter syndrome. The con­dition therefore is another example of nondisjeunction of X-chromosomes during meiosis. Like the autosomal trisomies, the risk of having a child with Klinefelter syndrome is higher in older mothers.


Most Klinefelter patients are sex chromatin positive, suggesting an XX constitution.

4.   The XYY syndrome. The karyotype formula is 47,XYY. The frequency of births is 1/2.000.

Phenotypic effects of the XYY  syndrome. These males are tall, fertile, lower intelligence and more aggressive than normal males.

 Etiology of the XYY  syndrome. Meiotic nondisjunction as a cause of 47,XYY necessarily occurs in the second division of the fathers. Mitotic nondisjunction in the early post-zygotic stages of development could give rise to mosaic 45,XO/47,XYY along with 46,XY cells. The 47,XYY cells, if they became the predominant type, might be responsible for a few cases classified simply as 47,XYY.

        Chromosomal mosaicism – an individual has  two or more cell types with different number of chromosomes. For example, 45,XO/46,XX.