1

Genes in Pedigrees and Populations

. .

 

  3
 (single gene disorders) 
(chromosomal disorders)  
 (multifactorial complex disorders) 
(pedigree) J
 
 J
(population genetics)

Genotype ( )    J

Phenotype ( ) 

Mendelian inheritance
  Gregor Mendel 
 (garden peas)   
Pedigree ()

 (family tree)  
Proband (propositus index case)  
  
J
Consultand
 
 
Sib


Kindred

Consanguinity
Allele ()   
wild type (mutation) 
mutant
Homozygote   homozygote
J
Heterozygote   heterozygote
J
Hemizygote  X 
X 1
  11
(Male)

(Female)

(Sex unspecified or unknown)

2

 (Unaffected)

 (Affected)

 (Obligate carrier)

Proband

(Deceased individual)
(Miscarriage)

(Stillbirth)

(Marriage)

(Consanguinity)

(Monozygotic twins)

(Dizygotic twins)

(Divorced)

 22
1
I

III

1
4

5
2

2
4

2
1

II

IV

1
1

' 2 proband, III-5 

 3 , III-3, III-4, III-7 3 (IV-3, IV-5 IV-6)
(first-degree relatives, 1)   8  2 (second-degree
relatives)  2  (grandparents) (uncles/aunts)
(nieces/nephews) IV-7 IV-8  
(generation) 
  J

' '

Victor A. McKusick  Mendelian Inheritance in Man  

 OMIM (Online Mendelian Inheritance in Man)3
OMIM   www.ncbi.nlm.nih.gov/Omim/  
J OMIM  10,000   

J  2
1.  (autosome)
X (X-linked)
2. (dominant) (recessive)
  
 (heterozygous) 
 J (homozygous)
J  4

- Autosomal dominant
- Autosomal recessive
- X-linked dominant
- X-linked recessive
 (http://www.geneclinics.org/)4, 5
J   

thalassemia  
Glucose-6-phosphate dehydrogenase  X
10 6
Autosomal dominant
   
 3

' 3  
J proband

  familial hypercholesterolemia 1 500 7
 (familial breast cancer hereditary colon
cancer) 1 300 8 
Neurofibromatosis Achondroplasia FGFRrelated craniosynostosis  Crouzon Apert Pfeiffer
Pfeiffer JJ
J FGFR1 FGFR29 infantile cortical hyperostosis
Caffey 2
J cortical hyperostosis
  10 
(familial cancer syndrome cancer inherited syndrome)
Multiple endocrine syndrome (MEN1)11 Bannayan-Riley-Ruvalcaba syndrome (BRRS)
Bannayan-Riley-Ruvalcaba syndrome (BRRS)  J 
J J J 
AVM (arteriovenous malformation)   12

1.   

2.   50 
 1
3.  J

4.  
5.  (isolated
case) (new mutation)  J
(gamete) 
   

   (new mutation) J2
' 1    Aa  
AA A  a 

' (AA)
(Gametes)
A
A
AA ()
AA ()
' A
a
Aa ( )
Aa ( )
(Aa)
 

1. New mutation
 
 
J
J  13

 Apert
JJ 14
osteogenesis imperfecta   15

 4 

' 4  osteogenesis imperfecta 

J 

  
  J
1 
50  5

' 5  
J proband   proband (new
mutation)  proband   proband
J  50
2. Reduced penetrance/nonpenetrance
  
J (heterozygous) 
 (skip
generation)    6
 
J
nonpenetrance penetrance () 
 penetrance
100  
 penetrance 100 
 J
 2

10

 nonpenetrance 
 J  
nonpenetrance J  
6   
 II-2  II-2
 J nonpenetrance


II

III

IV

' 6  
 II-2 (*) nonpenetrance
3. Variable expression
 
(clinical severity)  (age of onset) 
 
12, 16 J variable expression 

  J
(variable expression) 

11

  J

variable expression J

4. Germline mosaicism
Mosaicism  (cell line) J 2 J
 (postzygotic mutation) Mosaicism J
J (somatic) (germline) 
J 
 (de novo) J
J J
germline gonadal mosaicism J
 
 1
germline mosaicism 
 germline mosaicism osteogenesis imperfecta 
J (lethal)17 J  J
  germline
mosaicism J J
 
 germline mosaicism
J J  new mutation  J
 J germline mosaicism 3-4 J
(prenatal diagnosis)
J
Autosomal recessive
 
J J 2 homozygote J 
   
1 J 1 
 J  
 

12

 (carriers)
 7

' 7  

1.  1 

2.
3.  
4.   
 
J  8
5.   1 4 25

13

' 8   
   
 2  
 a  A
' 2  


'
Aa () x Aa ()
1/4 AA, Aa, 1/4 aa
3/4 1/4
Aa () x aa ( )
1/2 Aa, 1/2 aa
1/2 1/2
 
 (thalassemia)
 O  
 J 2 (homozygote)  (heterozygous
carrier) J

J  Pseudodominant  9

14

BO

OO

BO

OO

OO

BO

BO

OO

BO

OO

BO

' 9  O O

(pseudodominant pattern)

hemoglobinopathies thalassemia  cystic fibrosis 
(Caucasian) inborn error of metabolism  
 5- reductase (5-
reductase deficiency)18 (nephrogenic diabetes insipidus)19
X-linked recessive
1,400 X  40 
 X
1. J
2.  (heterozygous carriers)

 X-inactivation
3.   

4. X (no male to male transmission)
  J
50 
5.  (isolated cases) 
(new mutation)

15

X  X 2 1
 X
J dosage compensation  X-inactivation  
 Lyon hypothesis X 
(active)  X 1 
(inactive)   (Barr body) Xinactivation (random) X 
  
 J  skewed X-inactivation
X-inactivation 
 X
 X 

J 2 (homozygotes)   1
(heterozygote) skewed X-inactivation  J 
(mutant) X  (active X)   (wild type) X
 (inactive X)  J J
skewed X-inactivation  
(heterozygous carriers)  X
 X  
(hemophilia A) (hemophilia B) J Duchene muscular
dystrophy (DMD) Wiskott-Aldrich 2
 X 
 10

16

' 10  
X
 
X    3 X 
X  
h

' 3   X Y 
h

XX X  X 
h

(Gametes)
'
(XX)

X
X

' (X Y)
h

X
X X ()
h

Y
XY ()

h
XY ()
X X ()
     4

17

' 4  XY  
X X X  X 

(Gametes)
X
h
h
'
X X ()
X
h

' (XY)
Y
X Y ( )
XY ()
h

X X ()
X
 1 2 1 2  1
2 1 2
 X
(hemophilia A) (hemophilia B) J Duchene
muscular dystrophy (DMD) Wiskott-Aldrich chronic
granulomatous disease  X (X-linked CGD)
X-linked dominant
  X
(heterozygotes) J X (Xlinked dominant)  J 
 

 X  11
(X X)
h

18

' 11  
X
 X

1.    

2.  (heterozygote) 
 J 2  50 
3. 
(variable expression)
 X
J X-linked hypophosphatemic rickets  
 Incontinentia pigmenti Rett
 6 Goltz focal dermal hypoplasia
  20-22 Conradi-HnermannHapple syndrome Chondrodysplasia punctata type 2 (CDPX2)  
23, 24

19


X  J
 J (male lethal) 
J  12

' 12  
X  J (male lethal)
J  X 
 J  
 J  (heterozygote)
   X-inactivation 
Incontinentia pigmenti Rett Goltz focal dermal
hypoplasia20-22 Conradi-Hnermann-Happle syndrome Chondrodysplasia punctata
type 2 (CDPX2)23, 24
 EBP 
 13 J

 EBP J



20

' 13 EBP  
Chondrodysplasia punctata type 2 1
' (mitochondrial
inheritance)
(mitochondria) (organelle)  
(circular) 16.5
(mitochondrial DNA) 37   ribosomal RNA 2 transfer RNA
22 13   oxidative
phosphorylation  J

J  
J
1.  (cytoplasm)
(ovum)  
(zygote)  (sperm)
J 
J J
 J

21

J J
 maternal inheritance
 14

' 14  

2. J 
  J 
J   
(daughter cells) 
J  
 
 
 J homoplasmy J 
 J heteroplasmy J
 

 reduced penetrance, variable expression

22

pleiotropy (
)

 5
' 5 
'

Lebers hereditary optic neuropathy

NARP
Neuropathy, ataxia, retinitis pigmentosa

MELAS
Mitochondrial encephalomyopathy, lactic acidosis, and
strokelike episodes
J
MERRF
Myoclonic epilepsy, ragged red fibers (J)
J ataxia sensorineural deafness
CPEO
Chronic progressive external opthalmoplegia
J J
( Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson genetics in
medicine. 6th ed. Philadelphia. WB Saunders. 2004; 246.)

 
J  
 J

(Population genetics)
 
 J 
(mutation) (reproduction) 
(selection) (migration)

23

J

 
 
 J

founder effect J  J
(chance occurrence) genetic drift 
J (favorable mutation) selection
 (random mating)
  
 J  Hardy-Weinberg  J
 Geoffrey Hardy  Wilhelm Weinberg
. 1908  (genotype frequencies)
 (allele frequencies)25
Hardy-Weinberg (Hardy-Weinberg law)
 2 A a
 A p  a q  2 .
J p+q = 1 A a
J  A AA p2  a aa
q2  A a Aa 2pq  6
' 6   A a
 A p  a q

(Male gametes)
A (p)
a (q)
(Female gametes)
AA (p2)
Aa (pq)
A (p)
Aa (pq)
aa (q2)
a (q)
J  Hardy-Weinberg  AA,
Aa aa (binomial expansion)  (p+q)2 = p2+2pq+q2

24

 2  Hardy-Weinberg 
  
 J  AA, Aa aa  p2:2pq:q2
J
 7
' 7    
AA, Aa aa  p2:2pq:q2  Hardy-Weinberg

Mating type

AA
Aa
aa
AA x AA
P4
P4
AA x Aa
4p3q
2p3q
2p3q
Aa x Aa
4p2q2
p2q2
2p2q2
p2q2
AA x aa
2p2q2
2p2q2
Aa x aa
4pq3
2pq3
2pq3
aa x aa
q4
q4

p2(p2+2pq+q2)
2pq(p2+2pq+q2) q2(p2+2pq+q2)

p2
2pq
q2
J 
 J Hardy-Weinberg (Hardy-Weinberg equilibrium)
 J
 Hardy-Weinberg
    
Hardy-Weinberg J
 J 

 Hardy-Weinberg
1.
 (Non-random mating)
 J  
 (affected homozygote) 

- Assortative mating

25

2.

3.

  

   
J  
  (affected homozygote) J 
JJ
- Consanguinity

  (affected homozygote) J
(Mutation)
J Hardy-Weinberg
  J (mutant
allele) J  J
   
(reduced fitness) J
 Hardy-Weinberg
JJ

(Selection)
Hardy-Weinberg (seletion) 
 
(negative selection) (positive selection) J
 Hardy-Weinberg 
  (reduced
reproductive or biological fitness) 
J  
 (increased
reproductive or biological fitness) 
   1  (heterozygote)
 
(unaffected homozygote) J heterozygote advantage 
  sickle cell

26

4.

anemia26    (affected
homozygote)   
(sickle cell) 
   1 
(heterozygote) 
J J J plasmodium
falciparum     heterozygote
  J plasmodium falciparum
  J J
 J  
(endemic)  sickle cell
J  (unaffected homozygote)  
J plasmodium falciparum 
 (affected homozygote) 
J J  (heterozygote)
J   
(Small population size)
 J

J  
 J genetic drift 
 
 15

27

1.0-

0.8'

0.60.40.2-

0 (Generation) 0

1.00.8'

0.60.40.2-

00

3
4
5
6
(Generation)

' 15 genetic drift

( Turnpenny PD, Ellard, S. Emery's elements of medical genetics. 12th ed.
Philadelphia. Elsevier. 2005; 126.)

28

5.

Gene flow (migration)


 (migration)
 J  
 J J
gene flow   B  
  B  B
J
Hardy-Weinberg
 Hardy-Weinberg
 2 A a 
AA, Aa/aA aa   1000
J
AA 800
Aa/aA 185
aa 15
p ( A) q (
a) J  1000 1000x2 = 2000 (
, diploid) J
AA 800 Aa/aA 185 allele A 800x2 + 185 = 1785 J p = 0.8925
(1785/2000)
aa 15 Aa/aA 185 allele a 15x2 + 185 = 215 J q = 0.1075
(215/2000) q 1-p = 1-0.8925 = 0.1075
Hardy-Weinberg 
   (expected)
  J

' (Observed)
' (Expected)
AA
800
796.5 (p2x 1000)
Aa/aA
185
192 (2pq x 1000)
Aa
15
11.5 (q2x 1000)

(2)  

29

  2 D d  DD, Dd/dD
dd   1000  J
DD 430
Dd/dD 540
dd 30
p ( D) q (
d) J  1000 1000x2 = 2000 J DD 430
Dd/dD 540 allele D 430x2 + 540 = 1400 J p = 0.7 (1400/2000)
dd 30 Dd/dD 540 allele d 30x2 + 540 = 600 J q = 0.3 (600/2000)
q 1-p = 1-0.7 = 0.3
Hardy-Weinberg 
   (expected)
  J

DD
Dd/dD
Dd

' (Observed)
' (Expected)
430
490 (p2x 1000)
540
420 (2pq x 1000)
30
90 (q2x 1000)
   Dd/dD
  (observed)   (expected)
Hardy-Weinberg 
 J    Dd/dD
J heterozygote advantage 
Hardy-Weinberg  (carrier
frequency)  

1 2,500    (affected homozygotes) q2
  J
 J q   
1/2,500 0.0004 = 0.02 1 50  p+q = 1 J p = 0.98
49/50 J    2pq 2x49/50x1/50 = 0.04 1 25
J  p
1   2q 2x

30

 
J   
J

II
1

III
1

 II-2 
  2 3

A
a
AA
Aa
A
aA
aa
a
 II-2 2 
J (Aa) II-2 AA, Aa
aA J II-2  Aa aA 2 3
J  II-1 II-2
J J  
 II-1 x  II-2 x (
)
 II-1 2pq   II-2 2
3 J   2/3x2pqx1/4

31

J 
 8

?
' 8    
 

(q2)
' (2pq) 2/3x2pqx1/4
1 2,500
1 25
1 150
1 10,000
1 50
1 300
1 200,000
1 220
1 1,320

 J 
 J
 J
  

 
J
JJ  
J    J

32

1
Turnpenny PD & Ellard, S. (2005) Patterns of inheritance. Emery's elements of medical
genetics, 12th ed. Elsevier, Philadelphia.
2
Nussbaum RL, M.R., Willard HF (2004) Patterns of single-gene inheritance. Thompson
& Thompson genetics in medicine, 6th ed. WB Saunders, Philadelphia.
3
McKusick, V.A. (2007) Mendelian Inheritance in Man and its online version, OMIM. Am
J Hum Genet 80, 588-604.
4
Antonarakis, S.E. & McKusick, V.A. (2000) OMIM passes the 1,000-disease-gene mark.
Nat Genet 25, 11.
5
Hamosh, A., Scott, A.F., Amberger, J.S., Bocchini, C.A. & McKusick, V.A. (2005)
Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic
disorders. Nucleic Acids Res 33, D514-517.
6
Nuchprayoon, I., Sanpavat, S. & Nuchprayoon, S. (2002) Glucose-6-phosphate
dehydrogenase (G6PD) mutations in Thailand: G6PD Viangchan (871G>A) is the most common
deficiency variant in the Thai population. Hum Mutat 19, 185.
7
Jass, J.R. (2000) Familial colorectal cancer: pathology and molecular characteristics.
Lancet Oncol 1, 220-226.
8
Evans, D.G. & Lalloo, F. (2002) Risk assessment and management of high risk familial
breast cancer. J Med Genet 39, 865-871.
9
Shotelersuk, V., Srivuthana, S., Ittiwut, C., Theamboonlers, A., Mahatumarat, C. &
Poovorawan, Y. (2001) A case of Pfeiffer syndrome type 1 with an A344P mutation in the
FGFR2 gene. Southeast Asian J Trop Med Public Health 32, 425-428.
10
Suphapeetiporn, K., Tongkobpetch, S., Mahayosnond, A. & Shotelersuk, V. (2007)
Expanding the phenotypic spectrum of Caffey disease. Clin Genet 71, 280-284.
11
Suphapeetiporn, K., Greally, J.M., Walpita, D., Ashley, T. & Bale, A.E. (2002) MEN1
tumor-suppressor protein localizes to telomeres during meiosis. Genes Chromosomes Cancer 35,
81-85.
12
Suphapeetiporn, K., Kongkam, P., Tantivatana, J., Sinthuwiwat, T., Tongkobpetch, S. &
Shotelersuk, V. (2006) PTEN c.511C>T nonsense mutation in a BRRS family disrupts a potential
exonic splicing enhancer and causes exon skipping. Jpn J Clin Oncol 36, 814-821.

33

13
Rousseau, F., Saugier, P., Le Merrer, M., Munnich, A., Delezoide, A.L., Maroteaux, P.,
Bonaventure, J., Narcy, F. & Sanak, M. (1995) Stop codon FGFR3 mutations in thanatophoric
dwarfism type 1. Nat Genet 10, 11-12.
14
Renier, D., Arnaud, E., Cinalli, G., Sebag, G., Zerah, M. & Marchac, D. (1996)
Prognosis for mental function in Apert's syndrome. J Neurosurg 85, 66-72.
15
Byers, P.H. & Steiner, R.D. (1992) Osteogenesis imperfecta. Annu Rev Med 43, 269-282.
16
Carey, J.C. & Viskochil, D.H. (1999) Neurofibromatosis type 1: A model condition for
the study of the molecular basis of variable expressivity in human disorders. Am J Med Genet 89,
7-13.
17
Zlotogora, J. (1998) Germ line mosaicism. Hum Genet 102, 381-386.
18
Sahakitrungruang, T., Wacharasindhu, S., Yeetong, P., Snabboon, T., Suphapeetiporn, K.
& Shotelersuk, V. (2008) Identification of mutations in the SRD5A2 gene in Thai patients with
male pseudohermaphroditism. Fertil Steril.
19
Sahakitrungruang, T., Wacharasindhu, S., Sinthuwiwat, T., Supornsilchai, V.,
Suphapeetiporn, K. & Shotelersuk, V. (2008) Identification of two novel aquaporin-2 mutations
in a Thai girl with congenital nephrogenic diabetes insipidus. Endocrine 33, 210-214.
20
Grzeschik, K.H., Bornholdt, D., Oeffner, F., Konig, A., del Carmen Boente, M., Enders,
H., Fritz, B., Hertl, M., Grasshoff, U., Hofling, K., Oji, V., Paradisi, M., Schuchardt, C., Szalai,
Z., Tadini, G., Traupe, H. & Happle, R. (2007) Deficiency of PORCN, a regulator of Wnt
signaling, is associated with focal dermal hypoplasia. Nat Genet 39, 833-835.
21
Wang, X., Reid Sutton, V., Omar Peraza-Llanes, J., Yu, Z., Rosetta, R., Kou, Y.C., Eble,
T.N., Patel, A., Thaller, C., Fang, P. & Van den Veyver, I.B. (2007) Mutations in X-linked
PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet 39,
836-838.
22
Leoyklang, P., Suphapeetiporn, K., Wananukul, S. & Shotelersuk, V. (2008) Three novel
mutations in the PORCN gene underlying focal dermal hypoplasia. Clin Genet 73, 373-379.
23
Shotelersuk, V. & Tongkobpetch, S. (2005) Two novel frameshift mutations of the EBP
gene in two unrelated Thai girls with Conradi-Hunermann-Happle syndrome. Clin Exp Dermatol
30, 419-421.
24
Ausavarat, S., Tanpaiboon, P., Tongkobpetch, S., Suphapeetiporn, K. & Shotelersuk, V.
(2008) Two novel EBP mutations in Thai patients with Conradi-Hnermann-Happle syndrome.
Eur J Dermatol 18, 1-3.

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25
Turnpenny PD & Ellard, S. (2005) Mathematical and population genetics. Emery's
elements of medical genetics, 12th ed. Elsevier, Philadelphia.
26
Aidoo, M., Terlouw, D.J., Kolczak, M.S., McElroy, P.D., ter Kuile, F.O., Kariuki, S.,
Nahlen, B.L., Lal, A.A. & Udhayakumar, V. (2002) Protective effects of the sickle cell gene
against malaria morbidity and mortality. Lancet 359, 1311-1312.