1
00:00:15,000 --> 00:00:19,000
OK.  We are wrapping up our segment
on genetics today,

2
00:00:19,000 --> 00:00:24,000
Genetics 4.  We're going to talk
about human disease genetics,

3
00:00:24,000 --> 00:00:29,000
modes of inheritance for human
diseased genes.

4
00:00:29,000 --> 00:00:34,000
And then we'll transition next time
into molecular biology,

5
00:00:34,000 --> 00:00:38,000
which is the next blank square here.
And then recombinant DNA cell

6
00:00:38,000 --> 00:00:43,000
biology and beyond.
I wanted to start today by clearing

7
00:00:43,000 --> 00:00:48,000
up a couple of things.
Firstly, the term F1,

8
00:00:48,000 --> 00:00:52,000
in the last lecture I gave you a
list of terms,

9
00:00:52,000 --> 00:00:56,000
and I used this definition of the
first filial generation,

10
00:00:56,000 --> 00:01:01,000
the F1 generation as the product of
crosses between two homozygous

11
00:01:01,000 --> 00:01:05,000
individuals, homozygous for
different alleles such that the

12
00:01:05,000 --> 00:01:09,000
offspring were always heterozygous,
big A, little A at that particular

13
00:01:09,000 --> 00:01:14,000
gene.
Well, it turns out that some people

14
00:01:14,000 --> 00:01:18,000
use the term F1 to refer to the
offspring of any cross.

15
00:01:18,000 --> 00:01:22,000
So you have the parents and you
have the F1s regardless of the

16
00:01:22,000 --> 00:01:26,000
genotype of the parents.
So that's a looser definition of

17
00:01:26,000 --> 00:01:30,000
the term F1.  And it's been used in
Section and so on,

18
00:01:30,000 --> 00:01:33,000
so I didn't want to confuse you.
The strict definition is the one I

19
00:01:33,000 --> 00:01:37,000
told you, but don't get hung up on
that.  We're always going to give

20
00:01:37,000 --> 00:01:40,000
you the relevant genotypes so you'll
be able to figure out what the

21
00:01:40,000 --> 00:01:44,000
genotypes of the offspring are.
Also, near the end of the last

22
00:01:44,000 --> 00:01:47,000
lecture, I talked about crosses
involving linked genes.

23
00:01:47,000 --> 00:01:51,000
If you remember the Y and D gene
controlling color and density,

24
00:01:51,000 --> 00:01:54,000
I think, of peas.  And I told you
that they were linked,

25
00:01:54,000 --> 00:01:58,000
and we carried out a test cross.
And we then worked out what the

26
00:01:58,000 --> 00:02:02,000
percentages of the different
phenotypes and genotypes would be.

27
00:02:02,000 --> 00:02:05,000
Well, in that example,
I assumed that the Y allele and the

28
00:02:05,000 --> 00:02:09,000
D allele were together on the same
chromosome.  But importantly if

29
00:02:09,000 --> 00:02:12,000
you're just given the genotype as
it's written here,

30
00:02:12,000 --> 00:02:16,000
you actually cannot know that.
The big Y might be on the opposite

31
00:02:16,000 --> 00:02:20,000
chromosome from the big D.
So to avoid confusion about that

32
00:02:20,000 --> 00:02:23,000
sort of thing,
in future examples and in problems,

33
00:02:23,000 --> 00:02:27,000
problems, that is test questions,
we'll always show you the

34
00:02:27,000 --> 00:02:31,000
chromosomes so you'll know that the
genes are together on the same

35
00:02:31,000 --> 00:02:35,000
chromosome or on opposite.
Yeah.  And in the absence of this,

36
00:02:35,000 --> 00:02:40,000
if the question is to tell us what
the alleles must look like and they

37
00:02:40,000 --> 00:02:45,000
give you the phenotype,
you have to conclude the genotype.

38
00:02:45,000 --> 00:02:50,000
If the question is tell us what the
alleles must look like then we're

39
00:02:50,000 --> 00:02:55,000
not going to give you the answer,
but in other situations where

40
00:02:55,000 --> 00:03:00,000
there's ambiguity about what the
alignment might be, we'll

41
00:03:00,000 --> 00:03:04,000
tell you what that is.
OK?  We also had a question from a

42
00:03:04,000 --> 00:03:08,000
student, actually an emailed
question, those are also welcome,

43
00:03:08,000 --> 00:03:11,000
email question from a student.  It
was good question because in our

44
00:03:11,000 --> 00:03:15,000
discussion of dominance and
recessiveness,

45
00:03:15,000 --> 00:03:19,000
we really haven't dealt with the
molecular nature of that.

46
00:03:19,000 --> 00:03:22,000
And that was this individual's
interest.  Why is an allele dominant

47
00:03:22,000 --> 00:03:26,000
over another one?
Why is a trait dominant over

48
00:03:26,000 --> 00:03:29,000
another one?
And I gave an example to him,

49
00:03:29,000 --> 00:03:33,000
which I will give to you, which I
think covers most of the examples

50
00:03:33,000 --> 00:03:37,000
that we've been discussing in class.
And it also is an opportunity for

51
00:03:37,000 --> 00:03:41,000
me to reinforce the notions related
to chromosomes,

52
00:03:41,000 --> 00:03:44,000
genes, DNA and proteins,
because apparently there are some of

53
00:03:44,000 --> 00:03:48,000
you who are still a little fuzzy on
those relationships.

54
00:03:48,000 --> 00:03:52,000
So let's imagine a gene which is
present on a chromosome.

55
00:03:52,000 --> 00:03:56,000
Chromosome shown here.  Gene shown
here.  And it's the S gene that

56
00:03:56,000 --> 00:04:00,000
we've talked about before that
controls smooth versus

57
00:04:00,000 --> 00:04:04,000
wrinkled pea texture.
So here's the S gene.

58
00:04:04,000 --> 00:04:08,000
It's made up of DNA.  And based on
the sequence of that DNA within the

59
00:04:08,000 --> 00:04:12,000
gene, therein lies the information
to produce a protein.

60
00:04:12,000 --> 00:04:16,000
And we're going to call this
protein, in our example,

61
00:04:16,000 --> 00:04:20,000
this is a hypothetical example,
the starch synthase protein.  It's

62
00:04:20,000 --> 00:04:24,000
an enzyme that controls a reaction,
that catalyzes a reaction from some

63
00:04:24,000 --> 00:04:28,000
sugar substrate into some starch.
And if you make enough of that

64
00:04:28,000 --> 00:04:32,000
starch product then you
have a smooth shape.

65
00:04:32,000 --> 00:04:36,000
OK?  This enzyme controls shape
because it produces this product

66
00:04:36,000 --> 00:04:41,000
which is involved in the shape of a
pea.  OK?  So this is the normal

67
00:04:41,000 --> 00:04:46,000
situation.  The big S allele
produces a functional starch

68
00:04:46,000 --> 00:04:51,000
synthase enzyme which produces
enough product to give the pea its

69
00:04:51,000 --> 00:04:55,000
smooth shape.  In this example,
the little S allele, which is the

70
00:04:55,000 --> 00:05:00,000
recessive one,
has a mutation within the coding

71
00:05:00,000 --> 00:05:04,000
sequence of the gene.
We won't talk about the nature of

72
00:05:04,000 --> 00:05:07,000
that mutation just yet,
what it is, why it causes what it

73
00:05:07,000 --> 00:05:10,000
does because you're going to get
that in the next segment.

74
00:05:10,000 --> 00:05:13,000
Just suffice to say that it's a
mutation, an alteration of the DNA

75
00:05:13,000 --> 00:05:15,000
such that the protein that's
produced from this allele is

76
00:05:15,000 --> 00:05:18,000
nonfunctional.
You might be able to see I've

77
00:05:18,000 --> 00:05:21,000
inserted a little X there.
It's actually quite little and

78
00:05:21,000 --> 00:05:24,000
invisible on your handout,
but you might want to just circle it

79
00:05:24,000 --> 00:05:27,000
if you look carefully.
There's a little X there which is

80
00:05:27,000 --> 00:05:30,000
the result of this mutation.
And that X causes the protein to be

81
00:05:30,000 --> 00:05:34,000
nonfunctional.
The enzyme now does not catalyze

82
00:05:34,000 --> 00:05:38,000
the production of this starch
product, so no starch product is

83
00:05:38,000 --> 00:05:42,000
produced.  If you don't make the
starch product you don't have a

84
00:05:42,000 --> 00:05:46,000
smooth shape, you have a wrinkled
shape.  OK?  If the genotype of the

85
00:05:46,000 --> 00:05:50,000
pea is little S,
little S then none of this enzyme is

86
00:05:50,000 --> 00:05:54,000
produced such that none of the
starch product is produced such that

87
00:05:54,000 --> 00:05:58,000
the pea is wrinkled.
OK?  Now what happens if you're big

88
00:05:58,000 --> 00:06:02,000
S, little S, the heterozygote?
Well, for many biochemical reactions,

89
00:06:02,000 --> 00:06:07,000
having just one copy of the gene
that encodes the functional enzyme

90
00:06:07,000 --> 00:06:12,000
is enough.  For many biochemical
reactions that's true.

91
00:06:12,000 --> 00:06:16,000
And so in a situation where big S
is dominant over little S,

92
00:06:16,000 --> 00:06:21,000
we assume that having one copy of
big S makes enough of the starch

93
00:06:21,000 --> 00:06:26,000
synthase protein to make enough of
that starch product to give the pea

94
00:06:26,000 --> 00:06:31,000
its smooth shape.  OK?
So that's a simple example of why

95
00:06:31,000 --> 00:06:35,000
big S is dominant over little S,
why you only see the phenotype

96
00:06:35,000 --> 00:06:40,000
associated with the little S allele,
the wrinkled phenotype when you have

97
00:06:40,000 --> 00:06:44,000
two copies of the little S allele.
OK?  So I hope that helps clarify

98
00:06:44,000 --> 00:06:48,000
the situation for you and actually
is useful as we talk about human

99
00:06:48,000 --> 00:06:53,000
disease genes as well.
So this is a slide from your book

100
00:06:53,000 --> 00:06:57,000
which allows us to transition from
concepts of inheritance

101
00:06:57,000 --> 00:07:02,000
to real-life stuff.
Genes that regulate how your body

102
00:07:02,000 --> 00:07:06,000
functions normally or in response to
various environmental stresses.

103
00:07:06,000 --> 00:07:10,000
We're now in an era where we can
relatively easily figure out whether

104
00:07:10,000 --> 00:07:15,000
a disease has a genetic component by
looking at families that might have

105
00:07:15,000 --> 00:07:19,000
that disease, and based on that
information and using mapping

106
00:07:19,000 --> 00:07:23,000
techniques like I described to you
last time, we can isolate where that

107
00:07:23,000 --> 00:07:28,000
gene might lie on all
of your chromosomes.

108
00:07:28,000 --> 00:07:32,000
And then using molecular techniques,
which we'll talk about in future

109
00:07:32,000 --> 00:07:36,000
lectures, we can actually isolate
that gene, determine its sequence,

110
00:07:36,000 --> 00:07:40,000
and based on that produce lots of
various valuable things like better

111
00:07:40,000 --> 00:07:44,000
ways to diagnose the disease,
better ways to understand how the

112
00:07:44,000 --> 00:07:48,000
disease process takes place such
that we can then perhaps prevent the

113
00:07:48,000 --> 00:07:52,000
disease from occurring in the first
place or treating it more

114
00:07:52,000 --> 00:07:56,000
effectively by replacing the gene
with a new copy or producing a drug

115
00:07:56,000 --> 00:08:01,000
that can replace the
gene in other ways.

116
00:08:01,000 --> 00:08:06,000
So this is what we're after.
So we need to understand diseased

117
00:08:06,000 --> 00:08:12,000
genes and how they behave in such
affected families.

118
00:08:12,000 --> 00:08:17,000
So there are a number of diseases
which have a genetic component.

119
00:08:17,000 --> 00:08:23,000
And these diseases have various
modes of inheritance.

120
00:08:23,000 --> 00:08:36,000
Some of them are autosomal dominant.

121
00:08:36,000 --> 00:08:42,000
The diseased gene is dominant over
the wild type gene,

122
00:08:42,000 --> 00:08:48,000
and I'll give you examples of that.
And the term autosomal means that

123
00:08:48,000 --> 00:08:54,000
it's not sex linked.
That is the disease gene is carried

124
00:08:54,000 --> 00:09:00,000
on chromosomes 1 through 22,
one of the those chromosomes,

125
00:09:00,000 --> 00:09:06,000
not on the X or the Y.
It doesn't matter if your father,

126
00:09:06,000 --> 00:09:10,000
whether the disease gene is coming
from a male or a female,

127
00:09:10,000 --> 00:09:15,000
passed on to a daughter or a son.
There's no sex linkage for these

128
00:09:15,000 --> 00:09:19,000
autosomal dominant diseases.
There another class of genes,

129
00:09:19,000 --> 00:09:24,000
disease genes which follow autosomal
recessive inheritance patterns.

130
00:09:24,000 --> 00:09:29,000
Here the disease gene is recessive
to wild type.

131
00:09:29,000 --> 00:09:35,000
You only see the disease phenotype
when you're homozygous for the

132
00:09:35,000 --> 00:09:41,000
mutant allele.
And, again, autosomal because it's

133
00:09:41,000 --> 00:09:48,000
not sex linked.
There are X linked diseases which

134
00:09:48,000 --> 00:09:54,000
are dominant.  In this case,
the disease gene is on the X

135
00:09:54,000 --> 00:10:01,000
chromosome.  There are also X linked
diseases that are recessive.

136
00:10:01,000 --> 00:10:11,000
There are very few,

137
00:10:11,000 --> 00:10:15,000
but for the sake of completeness,
Y linked diseases.  But there are so

138
00:10:15,000 --> 00:10:20,000
few that we're actually not going to
talk about them at all in this class.

139
00:10:20,000 --> 00:10:24,000
And, finally,
there's a class of diseases that

140
00:10:24,000 --> 00:10:29,000
we're also not going to talk about
but get inherited not from the genes

141
00:10:29,000 --> 00:10:33,000
that are in the nucleus of the cell
along your chromosomes but rather

142
00:10:33,000 --> 00:10:38,000
get inherited from the
mitochondria.

143
00:10:38,000 --> 00:10:42,000
And since we haven't talked about
mitochondria with you really at all

144
00:10:42,000 --> 00:10:46,000
we're not going to expect you to
know about those diseases,

145
00:10:46,000 --> 00:10:50,000
but just have in the back of your
minds that those are relatively

146
00:10:50,000 --> 00:10:54,000
important.  Autosomal dominant
diseases are not terribly common.

147
00:10:54,000 --> 00:10:58,000
There are about 200 known.
Autosomal recessive diseases are

148
00:10:58,000 --> 00:11:02,000
actually much more common,
though not very frequent in the

149
00:11:02,000 --> 00:11:06,000
population.
There are about 2,

150
00:11:06,000 --> 00:11:12,000
00 of these known.  And together I
would estimate there are about 25

151
00:11:12,000 --> 00:11:18,000
sex linked diseases.
So we've used the term autosomal

152
00:11:18,000 --> 00:11:24,000
dominant, autosomal recessive,
sex linked.  What does this really

153
00:11:24,000 --> 00:11:30,000
look like in terms of the
genes and the alleles?

154
00:11:30,000 --> 00:11:43,000
Well, just as in the case of peas,

155
00:11:43,000 --> 00:11:48,000
a dominant disease allele will cause
disease regardless of the nature of

156
00:11:48,000 --> 00:11:54,000
the other allele.
It's dominant over the normal

157
00:11:54,000 --> 00:11:59,000
common version of the gene.
So if we call this allele the

158
00:11:59,000 --> 00:12:11,000
disease allele of some gene --

159
00:12:11,000 --> 00:12:16,000
-- and this allele the commonly
found on in the population,

160
00:12:16,000 --> 00:12:22,000
and we refer to these often as the
wild type --

161
00:12:22,000 --> 00:12:31,000
-- in an individual who has this

162
00:12:31,000 --> 00:12:37,000
genotype for a dominant disease gene,
will they develop disease?

163
00:12:37,000 --> 00:12:43,000
Yes, because the disease allele is
dominant over the normal copy of the

164
00:12:43,000 --> 00:12:49,000
gene.  So these individuals
will develop disease.

165
00:12:49,000 --> 00:13:04,000
For recessive disease alleles you

166
00:13:04,000 --> 00:13:08,000
need to have both copies,
both alleles be mutant in order to

167
00:13:08,000 --> 00:13:12,000
manifest the disease.
So here's another gene,

168
00:13:12,000 --> 00:13:16,000
which we'll call the H gene,
which has a disease allele.  This

169
00:13:16,000 --> 00:13:20,000
individual is homozygous for the
disease allele.

170
00:13:20,000 --> 00:13:24,000
Will this individual develop
disease?

171
00:13:24,000 --> 00:13:31,000
There might be other people in the

172
00:13:31,000 --> 00:13:35,000
population who are heterozygous for
that allele and have a wild type

173
00:13:35,000 --> 00:13:40,000
allele on the other chromosome.
Will they develop disease?  No.

174
00:13:40,000 --> 00:13:45,000
These individuals are called
heterozygous carriers.

175
00:13:45,000 --> 00:13:54,000
They carry the disease allele,

176
00:13:54,000 --> 00:13:58,000
but because they also carry a wild
type allele they don't develop the

177
00:13:58,000 --> 00:14:03,000
disease.  They're normal.
They're normal in the sense of their

178
00:14:03,000 --> 00:14:09,000
phenotype.  They have an abnormal
genotype in the sense that they have

179
00:14:09,000 --> 00:14:16,000
a disease allele,
but they're normal in the sense of

180
00:14:16,000 --> 00:14:23,000
their genotype,
phenotype.  Now,

181
00:14:23,000 --> 00:14:30,000
for X linked genes,
sorry, before I do that let me --

182
00:14:30,000 --> 00:14:35,000
Let me review for you sex
determination.

183
00:14:35,000 --> 00:14:40,000
We talked about this briefly.
In order to understand the

184
00:14:40,000 --> 00:14:45,000
inheritance pattern for X linked
genes you need to remember this.

185
00:14:45,000 --> 00:14:50,000
That males of course have one X
chromosome and one Y chromosome.

186
00:14:50,000 --> 00:14:55,000
Females have two X chromosomes.
If you think of a Punnett Square

187
00:14:55,000 --> 00:14:59,000
related to the inheritance of
chromosomes males will pass along an

188
00:14:59,000 --> 00:15:03,000
X or a Y at 50% each,
females will pass along one of their

189
00:15:03,000 --> 00:15:16,000
two Xs.

190
00:15:16,000 --> 00:15:22,000
Will produce an equal number of
males and females from such crosses.

191
00:15:22,000 --> 00:15:28,000
But it's important to think about
where the X chromosomes come from,

192
00:15:28,000 --> 00:15:34,000
specifically males and the Y
chromosomes.

193
00:15:34,000 --> 00:15:41,000
Males transmit their only Y,
their only Y to all of their sons.

194
00:15:41,000 --> 00:15:48,000
If you're the son then you've
gotten your father's only Y.

195
00:15:48,000 --> 00:15:56,000
Males transmit their only X
chromosome to all of

196
00:15:56,000 --> 00:16:06,000
their daughters.

197
00:16:06,000 --> 00:16:11,000
If you're the daughter,
when you're the daughter of a male,

198
00:16:11,000 --> 00:16:17,000
you have inherited his X chromosome.
OK?

199
00:16:17,000 --> 00:16:27,000
Females transmit either X to each

200
00:16:27,000 --> 00:16:35,000
daughter or son.
In the case of the female X,

201
00:16:35,000 --> 00:16:43,000
you can be a male who got this X
chromosome or a male who got this X

202
00:16:43,000 --> 00:16:51,000
chromosome.  You can be a female who
got this X chromosome or a female

203
00:16:51,000 --> 00:16:59,000
who got this X chromosome.
And that's important for

204
00:16:59,000 --> 00:17:05,000
understanding the disease genetics.
So let's imagine a dominant disease

205
00:17:05,000 --> 00:17:14,000
involving the X chromosome.

206
00:17:14,000 --> 00:17:20,000
A gene, we'll call it Q.
Males only have one X chromosome.

207
00:17:20,000 --> 00:17:27,000
They only have one X chromosome,
therefore if they carry the disease

208
00:17:27,000 --> 00:17:34,000
gene they're going
to get disease.

209
00:17:34,000 --> 00:17:38,000
Females have two X chromosomes.
They might carry the disease allele

210
00:17:38,000 --> 00:17:43,000
on one but a normal copy on the
other.  In this scenario,

211
00:17:43,000 --> 00:17:47,000
will they develop disease?
Yes, because it's a dominant

212
00:17:47,000 --> 00:18:00,000
disease allele.

213
00:18:00,000 --> 00:18:06,000
For recessive X linked disease,
once again, males only have one X.

214
00:18:06,000 --> 00:18:12,000
Are they going to get disease?  Yes.
Females have two X chromosomes.

215
00:18:12,000 --> 00:18:18,000
If they carry a disease allele on
one they are likely to carry a wild

216
00:18:18,000 --> 00:18:24,000
type copy on the other.
Are they going to get disease?

217
00:18:24,000 --> 00:18:31,000
No.  They're going to be
heterozygous carriers.

218
00:18:31,000 --> 00:18:38,000
And you'll see how this plays out

219
00:18:38,000 --> 00:18:46,000
towards the end of the lecture.

220
00:18:46,000 --> 00:18:51,000
OK.  So let's look at some examples.
We're going to start with recessive

221
00:18:51,000 --> 00:18:57,000
diseases first,
recessive autosomal diseases first.

222
00:18:57,000 --> 00:19:02,000
And one you've already seen before,

223
00:19:02,000 --> 00:19:08,000
and that's PKU, phenylketonuria.  If
you recall, this is a disease which

224
00:19:08,000 --> 00:19:14,000
is associated with failure to make
an enzyme that converts

225
00:19:14,000 --> 00:19:20,000
phenylalanine to tyrosine.
It's an enzyme called phenylalanine

226
00:19:20,000 --> 00:19:26,000
hydroxylase.  If you don't have that
enzyme then you produce too much of

227
00:19:26,000 --> 00:19:32,000
this byproduct,
phenylpyruvic acid which is toxic

228
00:19:32,000 --> 00:19:38,000
and leads to brain damage
and retardation.

229
00:19:38,000 --> 00:19:40,000
This can be avoided,
the disease can be avoided by

230
00:19:40,000 --> 00:19:43,000
limiting your amount of dietary
phenylalanine.

231
00:19:43,000 --> 00:19:46,000
And that's why such patients are
not supposed to have Equal,

232
00:19:46,000 --> 00:19:49,000
as we discussed before.  The disease,
PKU, is autosomal recessive.

233
00:19:49,000 --> 00:19:52,000
The incidence is rare, about one in
10,000 to 15,000 individuals have

234
00:19:52,000 --> 00:19:55,000
PKU.  As I talked to you about last
time, the mutant allele has a single

235
00:19:55,000 --> 00:19:58,000
amino acid chain change in the
active site of this enzyme which

236
00:19:58,000 --> 00:20:01,000
changes an arginine residue to a
tryptophan residue.

237
00:20:01,000 --> 00:20:05,000
And that makes the enzyme inactive.
This is an autosomal recessive

238
00:20:05,000 --> 00:20:10,000
disease.  So if you have one mutant
allele and one normal copy of the

239
00:20:10,000 --> 00:20:15,000
phenylalanine hydroxylase gene,
do you have the disease?  No.  You

240
00:20:15,000 --> 00:20:20,000
would be a carrier but you would not
have the disease symptoms.

241
00:20:20,000 --> 00:20:25,000
Because again, as in the other
hypothetical example,

242
00:20:25,000 --> 00:20:29,000
most of the time, if you have a
single normal copy of an enzyme that

243
00:20:29,000 --> 00:20:34,000
carries out some biochemical
reaction that's enough and your

244
00:20:34,000 --> 00:20:39,000
phenotype is normal.
Here's another common example,

245
00:20:39,000 --> 00:20:43,000
cystic fibrosis.  This is actually a
more common disease.

246
00:20:43,000 --> 00:20:47,000
It affects about one in 2,
00 to 3,000 individuals.  That's not

247
00:20:47,000 --> 00:20:51,000
an insignificant number.
So there are a lot of people with

248
00:20:51,000 --> 00:20:55,000
cystic fibrosis in this country.
Again, it's autosomal recessive.

249
00:20:55,000 --> 00:20:59,000
Patients present with the disease
at birth.

250
00:20:59,000 --> 00:21:03,000
They have problems both in their
intestinal system as well as in

251
00:21:03,000 --> 00:21:07,000
their lungs.  It tends to be the
lung symptoms that ultimately kills

252
00:21:07,000 --> 00:21:11,000
the patient due to inability to
breathe properly,

253
00:21:11,000 --> 00:21:15,000
but actually more importantly
persistent infections which

254
00:21:15,000 --> 00:21:19,000
ultimately are so severe that they
lead to death.

255
00:21:19,000 --> 00:21:23,000
And these patients tend to die
within the first two to three

256
00:21:23,000 --> 00:21:27,000
decades of life.
The gene encoded by the disease,

257
00:21:27,000 --> 00:21:31,000
the gene responsible for this
disease is a chloride channel.

258
00:21:31,000 --> 00:21:34,000
When it functions properly it allows
chloride ions to move through,

259
00:21:34,000 --> 00:21:38,000
and this achieves a proper water
balance inside the cells.

260
00:21:38,000 --> 00:21:41,000
When the disease allele is present
in both copies,

261
00:21:41,000 --> 00:21:45,000
this channel is not formed properly,
and therefore the water balance in

262
00:21:45,000 --> 00:21:49,000
such cells is not correct and it
leads to the build up of this kind

263
00:21:49,000 --> 00:21:52,000
of mucousy sticky substance both in
the lungs and in the intestines.

264
00:21:52,000 --> 00:21:56,000
These individuals, as you can see,
have a very hard time breathing, and

265
00:21:56,000 --> 00:22:00,000
they have to get this mucous cleared
from their lungs periodically.

266
00:22:00,000 --> 00:22:04,000
And they also often have to have
respirators to allow them to breath.

267
00:22:04,000 --> 00:22:08,000
OK.  So that's some examples of
autosomal recessive diseases.

268
00:22:08,000 --> 00:22:13,000
Let's think about the genetics.
And we'll talk about CF

269
00:22:13,000 --> 00:22:17,000
specifically.  Let's imagine the
disease allele of CF.

270
00:22:17,000 --> 00:22:22,000
We'll call it CFD.  There are
actually many different disease

271
00:22:22,000 --> 00:22:26,000
alleles for this disease,
but we'll just lump them together.

272
00:22:26,000 --> 00:22:33,000
Here are two individuals with this

273
00:22:33,000 --> 00:22:41,000
genotype.  Do these individuals
manifest the disease?

274
00:22:41,000 --> 00:22:49,000
Yes or no?  Do they manifest the
disease?  No, because this is an

275
00:22:49,000 --> 00:22:58,000
autosomal recessive disease and they
have a wild type copy.

276
00:22:58,000 --> 00:23:03,000
But if we think about the offspring
that they could produce,

277
00:23:03,000 --> 00:23:09,000
this individual will produce gametes
that carry the D allele and the wild

278
00:23:09,000 --> 00:23:15,000
type allele, likewise this
individual, the D allele and the

279
00:23:15,000 --> 00:23:21,000
wild type allele,
such that the offspring will either

280
00:23:21,000 --> 00:23:27,000
be DD, wild type D,
wild type, wild type or wild type,

281
00:23:27,000 --> 00:23:32,000
D.  Right?
So you'll have one wild type,

282
00:23:32,000 --> 00:23:37,000
wild type individual produced out of
such a cross.  And this individual

283
00:23:37,000 --> 00:23:42,000
now has no disease allele present.
This individual is both

284
00:23:42,000 --> 00:23:47,000
genotypically and phenotypically
normal.  No more issues about cystic

285
00:23:47,000 --> 00:23:52,000
fibrosis for this person or his or
her descendants.

286
00:23:52,000 --> 00:23:57,000
There will be two individuals who
are heterozygous,

287
00:23:57,000 --> 00:24:02,000
and these individuals are carriers.
They don't have the disease but they

288
00:24:02,000 --> 00:24:07,000
do have a mutant allele.
So depending on whom they marry,

289
00:24:07,000 --> 00:24:12,000
I shouldn't generalize, depending on
whom they have children with they

290
00:24:12,000 --> 00:24:17,000
may or may not have to worry about
the fact that they have a mutant CF

291
00:24:17,000 --> 00:24:22,000
allele.  And one,
on average, out of four will have

292
00:24:22,000 --> 00:24:28,000
two disease alleles and
develop CF.  OK?

293
00:24:28,000 --> 00:24:38,000
So we're going to now think about

294
00:24:38,000 --> 00:24:42,000
these diseases in inheritance
looking at pedigrees,

295
00:24:42,000 --> 00:24:46,000
which I think are probably familiar
to most of you.

296
00:24:46,000 --> 00:24:50,000
They're described in your book as
well.  But I just want to make sure

297
00:24:50,000 --> 00:24:54,000
you understand what the symbols mean
before we get into it.

298
00:24:54,000 --> 00:24:58,000
Females are represented as circles.
Males are represented as squares.

299
00:24:58,000 --> 00:25:03,000
Seems appropriate.
Lines between them represent a

300
00:25:03,000 --> 00:25:09,000
mating, they have mated.
And the offspring are represented

301
00:25:09,000 --> 00:25:21,000
below.

302
00:25:21,000 --> 00:25:27,000
If the symbol is left open then the
individual is normal,

303
00:25:27,000 --> 00:25:34,000
genotypically and phenotypically.
If the individual has a shaded

304
00:25:34,000 --> 00:25:41,000
symbol they are affected,
they show disease symptoms.

305
00:25:41,000 --> 00:25:48,000
And if the symbol is partially
shaded, I usually fill in half the

306
00:25:48,000 --> 00:25:55,000
symbol, the book will sometimes put
a little circle inside the circle

307
00:25:55,000 --> 00:26:02,000
then they are carriers.
They're heterozygous carriers.

308
00:26:02,000 --> 00:26:07,000
OK?  So let's look and think about
this example up here.

309
00:26:07,000 --> 00:26:13,000
We talked about two individuals who
were both heterozygous for the

310
00:26:13,000 --> 00:26:19,000
disease allele,
so they were carriers.

311
00:26:19,000 --> 00:26:25,000
Their genotype was CFD,
CF wild type.

312
00:26:25,000 --> 00:26:32,000
They mated.  They had

313
00:26:32,000 --> 00:26:42,000
four children.

314
00:26:42,000 --> 00:26:46,000
There were four possible genotypes,
rather three possible genotypes.

315
00:26:46,000 --> 00:26:51,000
And, in fact, we observe all three
genotypes in this generation.

316
00:26:51,000 --> 00:26:55,000
We have one individual over here who
doesn't have her symbol filled.

317
00:26:55,000 --> 00:27:00,000
We have another whose symbol is
fully filled.

318
00:27:00,000 --> 00:27:08,000
And then we have two whose symbols
are partially filled.

319
00:27:08,000 --> 00:27:16,000
What's the genotype of this
individual?  Wild type,

320
00:27:16,000 --> 00:27:24,000
wild type.  This one?  D,
D.  This one?  D, wild type.

321
00:27:24,000 --> 00:27:32,000
And this one?  Same thing.  OK?
So that's what pedigrees look like.

322
00:27:32,000 --> 00:27:37,000
Let me show you a larger pedigree
and give you some of the rules that

323
00:27:37,000 --> 00:27:43,000
apply to autosomal recessive
diseases.  So here's a large

324
00:27:43,000 --> 00:27:49,000
pedigree involving an autosomal
recessive gene,

325
00:27:49,000 --> 00:27:55,000
disease gene.  Again,
the two parents are heterozygous.

326
00:27:55,000 --> 00:28:01,000
They had many, many offspring all
here.  Roughly a quarter of them

327
00:28:01,000 --> 00:28:07,000
will carry both copies of the
disease gene and develop disease.

328
00:28:07,000 --> 00:28:11,000
Among the rest there will be
unaffected individuals but of two

329
00:28:11,000 --> 00:28:16,000
classes, ones that don't have the
disease gene at all and ones who are

330
00:28:16,000 --> 00:28:20,000
heterozygous carriers.
Two-thirds of those unaffected

331
00:28:20,000 --> 00:28:25,000
offspring are themselves carriers,
two-thirds.  Two-thirds of the

332
00:28:25,000 --> 00:28:30,000
unaffected offspring are
themselves carriers.

333
00:28:30,000 --> 00:28:34,000
Among those half of the offspring of
a carrier are themselves carriers,

334
00:28:34,000 --> 00:28:39,000
as shown here.  So if this
individual came to you at a genetics

335
00:28:39,000 --> 00:28:44,000
clinic and wanted to know what is my
likelihood of carrying the D mutant

336
00:28:44,000 --> 00:28:49,000
allele, you'd be able to say,
without knowing the genotype of his

337
00:28:49,000 --> 00:28:54,000
mother you would be able to say that
it's half of a half

338
00:28:54,000 --> 00:28:58,000
or a quarter.  OK?
Now, every once in a while two

339
00:28:58,000 --> 00:29:02,000
affected individuals,
two homozygotes have children,

340
00:29:02,000 --> 00:29:06,000
as shown here.  And you can see in
that scenario all of the offspring

341
00:29:06,000 --> 00:29:09,000
have disease because the only
alleles that are present are the

342
00:29:09,000 --> 00:29:13,000
mutant alleles.
That has to be true because these

343
00:29:13,000 --> 00:29:17,000
are both affected,
and therefore all of the offspring

344
00:29:17,000 --> 00:29:21,000
will also only inherit mutant
alleles and develop the disease

345
00:29:21,000 --> 00:29:25,000
themselves.  OK?
And importantly because the disease

346
00:29:25,000 --> 00:29:31,000
gene is coming in on chromosomes 1
to 22, one of those and not the X or

347
00:29:31,000 --> 00:29:37,000
the Y, there is no gender
associations here.

348
00:29:37,000 --> 00:29:43,000
Mothers can pass the disease to
their daughters and their sons.

349
00:29:43,000 --> 00:29:49,000
Fathers can pass the disease to
their daughters and their sons.

350
00:29:49,000 --> 00:29:55,000
There are no gender associations
with this scenario.

351
00:29:55,000 --> 00:29:58,000
OK.  Disease alleles are present in
different frequencies in the

352
00:29:58,000 --> 00:30:02,000
population.  Some of them are
extremely rare,

353
00:30:02,000 --> 00:30:06,000
but some of them are actually rather
common.

354
00:30:06,000 --> 00:30:16,000
So we're talking about the allele

355
00:30:16,000 --> 00:30:21,000
frequency, the percentage of alleles
among all of our chromosomes that

356
00:30:21,000 --> 00:30:27,000
are the disease type.
For PKU it depends a lot on where

357
00:30:27,000 --> 00:30:34,000
you're from.
For example, in Turkey it's actually

358
00:30:34,000 --> 00:30:42,000
rather common,
one in 206,000 alleles of this gene

359
00:30:42,000 --> 00:30:51,000
are mutant in this population,
but in Japan it's much less common.

360
00:30:51,000 --> 00:31:00,000
One in 220,000 Japanese carry this
allele.

361
00:31:00,000 --> 00:31:04,000
Exactly why this is we're not
entirely sure,

362
00:31:04,000 --> 00:31:08,000
although I'll give you some
speculation in a little while about

363
00:31:08,000 --> 00:31:13,000
what controls the frequency of these
actually rather deleterious alleles.

364
00:31:13,000 --> 00:31:17,000
CF is fairly frequent.  One in 25
alleles are CF.

365
00:31:17,000 --> 00:31:22,000
One in 25.  There are as maybe 200
of you in this room,

366
00:31:22,000 --> 00:31:26,000
so that's some number of mutant
alleles among you.  It's

367
00:31:26,000 --> 00:31:31,000
a fairly high number.
You're sitting there carrying a

368
00:31:31,000 --> 00:31:37,000
mutant copy of the CF allele.
This is actually relevant to

369
00:31:37,000 --> 00:31:42,000
European descendancy.
I'm not entirely sure whether it

370
00:31:42,000 --> 00:31:48,000
applies to all descendencies but
let's just say that it's roughly

371
00:31:48,000 --> 00:31:53,000
that number.  And another disease
that you might have heard of

372
00:31:53,000 --> 00:31:59,000
Tay-Sachs disease in the Ashkenazi
Jewish population --

373
00:31:59,000 --> 00:32:08,000
-- is also quite common.

374
00:32:08,000 --> 00:32:13,000
One in 25. It's so common,
in fact, that in certain parts of

375
00:32:13,000 --> 00:32:19,000
the world individuals undergo
genetic testing before they decide

376
00:32:19,000 --> 00:32:24,000
whom to date because they want to
avoid the risk that they're going to

377
00:32:24,000 --> 00:32:30,000
date somebody else who carries
such a mutation.

378
00:32:30,000 --> 00:32:33,000
This is actually a very horrible
disease.  I shouldn't joke about it.

379
00:32:33,000 --> 00:32:37,000
So they want to avoid ever having
to face the problem of having a

380
00:32:37,000 --> 00:32:41,000
child who has Tay-Sachs disease.
So they undergo, in a sense,

381
00:32:41,000 --> 00:32:45,000
pre-marriage counseling to figure
out their genotype to decide whether

382
00:32:45,000 --> 00:32:49,000
or not to date.
And you can also imagine with

383
00:32:49,000 --> 00:32:53,000
similar tests we could figure out
whether or not individuals carry

384
00:32:53,000 --> 00:32:57,000
mutations in these genes to let them
know what their risks of developing

385
00:32:57,000 --> 00:33:01,000
disease are or whether or not to
maintain a pregnancy of a child who

386
00:33:01,000 --> 00:33:05,000
may or may not be affected
and so on.

387
00:33:05,000 --> 00:33:09,000
So they're very serious societal
implications for these kinds of

388
00:33:09,000 --> 00:33:14,000
disease alleles.
Now, some of the alleles are very

389
00:33:14,000 --> 00:33:18,000
rare.  Here's one example in the
Japanese population of PKU.

390
00:33:18,000 --> 00:33:23,000
The likelihood that two individuals
would randomly get together who had

391
00:33:23,000 --> 00:33:27,000
mutant alleles of a phenylalanine
hydroxylase gene and have a child is

392
00:33:27,000 --> 00:33:32,000
exceedingly small.
And so in these situations,

393
00:33:32,000 --> 00:33:37,000
where the allele frequency is
extremely rare,

394
00:33:37,000 --> 00:33:42,000
when you find an affected individual
it's almost always a sure sign of

395
00:33:42,000 --> 00:33:47,000
inbreeding.  Consanguinity is the
term used in genetics where cousins

396
00:33:47,000 --> 00:33:52,000
or other relatives marry and have
children.  And since they are

397
00:33:52,000 --> 00:33:57,000
related and have a higher allele
frequency within their families of a

398
00:33:57,000 --> 00:34:02,000
particular allele then the
likelihood that they'll have an

399
00:34:02,000 --> 00:34:07,000
offspring who has two copies of the
allele is much higher.

400
00:34:07,000 --> 00:34:11,000
And so when you see a pattern such
as this, it's a fairly clear

401
00:34:11,000 --> 00:34:16,000
indication that you're dealing with
an autosomal recessive disease

402
00:34:16,000 --> 00:34:21,000
involving consanguineous mating.
Here are two cousins who are

403
00:34:21,000 --> 00:34:26,000
producing offspring both of whom are
affected.  And when you see a

404
00:34:26,000 --> 00:34:31,000
pattern like this you can actually
figure out, or at least figure out

405
00:34:31,000 --> 00:34:36,000
pretty well who were the carriers in
this scenario,

406
00:34:36,000 --> 00:34:41,000
who were the carriers in this family.
Since both, since the children have

407
00:34:41,000 --> 00:34:46,000
two mutant copies then both of their
parents must be heterozygous

408
00:34:46,000 --> 00:34:50,000
carriers.  OK?
That goes without saying.

409
00:34:50,000 --> 00:34:55,000
They're heterozygous.  Since this
individual is heterozygous and the

410
00:34:55,000 --> 00:35:00,000
allele was passed on from their
grandparents then his mother must

411
00:35:00,000 --> 00:35:05,000
also carry the allele inherited from
one of the two grandparents.

412
00:35:05,000 --> 00:35:09,000
Likewise this woman's father must
carry the mutant allele.

413
00:35:09,000 --> 00:35:13,000
And in this generation we actually
don't know whether it's the male or

414
00:35:13,000 --> 00:35:17,000
the female who carries the mutation.
It could be either.  And it's been

415
00:35:17,000 --> 00:35:22,000
passed along to both sides of this
family tree and reduced to

416
00:35:22,000 --> 00:35:26,000
homozygocity in this generation.
OK?  You can also begin to figure

417
00:35:26,000 --> 00:35:30,000
out what the likelihood of other
members of the family tree

418
00:35:30,000 --> 00:35:35,000
is being heterozygous.
So this individual here has a one in

419
00:35:35,000 --> 00:35:39,000
two chance. One of these two parents
is definitely a heterozygote,

420
00:35:39,000 --> 00:35:43,000
and so the likelihood that he's a
heterozygote is one in two.

421
00:35:43,000 --> 00:35:47,000
And among his children you could
say they have a one in four chance.

422
00:35:47,000 --> 00:35:51,000
If he has a one in two chance then
there's a one in two chance that

423
00:35:51,000 --> 00:35:55,000
he'll pass it onto them,
so overall there's a one in four

424
00:35:55,000 --> 00:35:59,000
chance that they will be
themselves carriers.

425
00:35:59,000 --> 00:36:03,000
And this, again,
this kind of genetic testing is done

426
00:36:03,000 --> 00:36:07,000
frequently to figure out what your
relative risk of developing a

427
00:36:07,000 --> 00:36:11,000
particular disease are.
Now, as I said, for other disease

428
00:36:11,000 --> 00:36:16,000
alleles like CF and Tay-Sachs,
the allele frequency is actually

429
00:36:16,000 --> 00:36:20,000
strikingly high.
And yet if you're homozygous for

430
00:36:20,000 --> 00:36:24,000
these mutations you're dead.
Not necessarily right away but not

431
00:36:24,000 --> 00:36:28,000
for very long.
It clearly reduces your

432
00:36:28,000 --> 00:36:33,000
reproductive fitness.
And so why would these alleles be

433
00:36:33,000 --> 00:36:37,000
present in our population at all?
Why wouldn't they be removed

434
00:36:37,000 --> 00:36:41,000
through natural selection?
We're not going to get into this in

435
00:36:41,000 --> 00:36:45,000
great detail, but there are theories
out there and some evidence to

436
00:36:45,000 --> 00:36:49,000
support them that there might be
actually an advantage in certain

437
00:36:49,000 --> 00:36:53,000
circumstances for being heterozygous
wild type over mutant.

438
00:36:53,000 --> 00:36:57,000
And there are theories both related
to Tay-Sachs disease,

439
00:36:57,000 --> 00:37:01,000
sickle cell disease and cystic
fibrosis such that if you are

440
00:37:01,000 --> 00:37:05,000
heterozygous you actually survive
better in the face of certain

441
00:37:05,000 --> 00:37:10,000
pathogenic exposure than do people
who are wild type for both alleles.

442
00:37:10,000 --> 00:37:14,000
And that's the argument for why
these alleles actually built up,

443
00:37:14,000 --> 00:37:19,000
at least in the past, over the
evolution of our species.

444
00:37:19,000 --> 00:37:24,000
OK.  Let's transition now to
autosomal dominant diseases.

445
00:37:24,000 --> 00:37:29,000
This is a famous example,
Huntington's disease,

446
00:37:29,000 --> 00:37:33,000
otherwise called Huntington's chorea.
Relatively rare.

447
00:37:33,000 --> 00:37:37,000
About one in 10,
00 to 25,000 individuals affected.

448
00:37:37,000 --> 00:37:41,000
It exhibits an autosomal dominant
pattern of inheritance,

449
00:37:41,000 --> 00:37:45,000
as you'll see in a moment.
The age of onset is about 35 to 40

450
00:37:45,000 --> 00:37:49,000
years of age.  These individuals
actually are totally normal for the

451
00:37:49,000 --> 00:37:53,000
first three to four decades.
You wouldn't know that they had a

452
00:37:53,000 --> 00:37:57,000
disease.  But starting at that time
they begin to develop symptoms which

453
00:37:57,000 --> 00:38:01,000
involve both effects on their
personalities but more importantly

454
00:38:01,000 --> 00:38:05,000
effects on their movements.
That's what you first begin to see.

455
00:38:05,000 --> 00:38:09,000
That's what chorea means.  It's
sort of this dance-like movement.

456
00:38:09,000 --> 00:38:14,000
And then that gets much, much more
severe and stereotypical.

457
00:38:14,000 --> 00:38:18,000
And eventually, in addition to that,
there's death of cells in the brain.

458
00:38:18,000 --> 00:38:23,000
And the combination of these
affects leads to the death of the

459
00:38:23,000 --> 00:38:28,000
individual by about the fourth or
fifth decade of life.

460
00:38:28,000 --> 00:38:32,000
This is actually a movie of an
individual who has Huntington's

461
00:38:32,000 --> 00:38:37,000
disease.
He's being told to hold his arms

462
00:38:37,000 --> 00:38:41,000
straight out, but because of this
neurogenerative process that's

463
00:38:41,000 --> 00:38:46,000
taking place within his brain and
also other parts of his nervous

464
00:38:46,000 --> 00:38:50,000
system he's unable to do so.
And this is sort of the

465
00:38:50,000 --> 00:38:55,000
stereotypical presentation of
Huntington's chorea.

466
00:38:55,000 --> 00:38:59,000
They have this wave-like movement
and also their limbs get stuck in

467
00:38:59,000 --> 00:39:04,000
particular postures,
as you can see this individual here.

468
00:39:04,000 --> 00:39:07,000
At the molecular level the problem
in these individuals is that their

469
00:39:07,000 --> 00:39:11,000
brain cells are dying,
particular ones, actually,

470
00:39:11,000 --> 00:39:14,000
within a particular region of the
brain surrounding this ventricle

471
00:39:14,000 --> 00:39:18,000
here.  And this is a normal space in
a normal brain.

472
00:39:18,000 --> 00:39:22,000
And there are various sets of
neurons on either side of those

473
00:39:22,000 --> 00:39:25,000
ventricles.  And in HD patients
those cells are progressively lost

474
00:39:25,000 --> 00:39:29,000
over time, and when those cells are
lost you lose motor control and you

475
00:39:29,000 --> 00:39:33,000
also develop rather
severe dementia.

476
00:39:33,000 --> 00:39:37,000
And the reason that those cells are
being lost is that the mutant

477
00:39:37,000 --> 00:39:41,000
protein, the mutant form of this
protein called Huntington,

478
00:39:41,000 --> 00:39:45,000
the mutant form builds up inside of
those cells and aggregates and

479
00:39:45,000 --> 00:39:49,000
causes the cells to die.
OK?  And this is why this is an

480
00:39:49,000 --> 00:39:53,000
autosomal dominant disease.
If you have the disease allele then

481
00:39:53,000 --> 00:39:57,000
you will get the aggregation of the
protein and you will develop

482
00:39:57,000 --> 00:40:07,000
the disease.

483
00:40:07,000 --> 00:40:14,000
So let's take another example of a
cross between an individual who is

484
00:40:14,000 --> 00:40:22,000
normal, two normal copies of HD and
an individual who has a disease

485
00:40:22,000 --> 00:40:30,000
allele and a wild type allele who is
heterozygous.  Is this

486
00:40:30,000 --> 00:40:36,000
individual diseased?
He either is already or he will be

487
00:40:36,000 --> 00:40:40,000
in the case of HD.
It's an autosomal dominant disease.

488
00:40:40,000 --> 00:40:44,000
If you have the disease allele you
will develop disease.

489
00:40:44,000 --> 00:40:48,000
If we look at a Punnett Square,
this individual will always transmit

490
00:40:48,000 --> 00:40:53,000
the wild type allele,
this individual will transmit the

491
00:40:53,000 --> 00:40:57,000
mutant allele half the time the wild
type allele of the other.

492
00:40:57,000 --> 00:41:01,000
These individuals will be wild type
D, wild type D,

493
00:41:01,000 --> 00:41:06,000
wild type, wild type,
wild type, wild type.

494
00:41:06,000 --> 00:41:13,000
So you'll get half diseased,
half normal.  OK?  A rather

495
00:41:13,000 --> 00:41:21,000
different picture than we saw
previously.  And importantly,

496
00:41:21,000 --> 00:41:29,000
as I mentioned, the presence, the
mere presence of the D allele leads

497
00:41:29,000 --> 00:41:37,000
to the production of
this toxic protein.

498
00:41:37,000 --> 00:41:43,000
And ultimately brain damage.
And that's why it's dominant.

499
00:41:43,000 --> 00:41:49,000
OK.  So let's look at a pedigree of
an autosomal dominant disorder.

500
00:41:49,000 --> 00:41:55,000
Here's an affected individual, a
female who marries,

501
00:41:55,000 --> 00:42:02,000
who has children with an unaffected
male.

502
00:42:02,000 --> 00:42:06,000
They have four children.
On average half of them will

503
00:42:06,000 --> 00:42:10,000
inherit the defective allele and
therefore develop disease.

504
00:42:10,000 --> 00:42:14,000
Half of the offspring of an
affected parent will be affected.

505
00:42:14,000 --> 00:42:19,000
Importantly, the unaffected
offspring of an affected parent have

506
00:42:19,000 --> 00:42:23,000
unaffected offspring.
If you are normal, you do not

507
00:42:23,000 --> 00:42:27,000
inherit the disease allele,
you're scot-free. Your children will

508
00:42:27,000 --> 00:42:32,000
no longer have to worry
about this disease.

509
00:42:32,000 --> 00:42:35,000
But in this case,
in this individual,

510
00:42:35,000 --> 00:42:38,000
again roughly half, in this example
two-thirds of the offspring do

511
00:42:38,000 --> 00:42:42,000
develop the disease.
This is another really important

512
00:42:42,000 --> 00:42:45,000
case of genetic testing.
This guy might have wanted to know

513
00:42:45,000 --> 00:42:49,000
that he was going to develop
Huntington's disease in order to

514
00:42:49,000 --> 00:42:52,000
decide whether to have children in
the first place.

515
00:42:52,000 --> 00:42:55,000
This individual here likewise might
want to know before the disease

516
00:42:55,000 --> 00:42:59,000
actually manifested itself what
would happen in order to make

517
00:42:59,000 --> 00:43:02,000
lifestyle decisions.
Am I going to quit work and have a

518
00:43:02,000 --> 00:43:06,000
good time for the next ten years?
Because pretty soon I'm actually

519
00:43:06,000 --> 00:43:10,000
not going to be able to.
So genetic testing actually can

520
00:43:10,000 --> 00:43:13,000
make an extremely important set of
decisions for individuals affected

521
00:43:13,000 --> 00:43:17,000
in this way.  And there's actually a
subtlety here,

522
00:43:17,000 --> 00:43:20,000
too.  Sometimes people don't want to
know because there's actually

523
00:43:20,000 --> 00:43:24,000
nothing to be done for them.
In the case of Huntington's disease

524
00:43:24,000 --> 00:43:28,000
that's true.  We don't
have a cure for it.

525
00:43:28,000 --> 00:43:32,000
So Arlo Guthrie who is the son of
Woody Guthrie,

526
00:43:32,000 --> 00:43:36,000
who died of Huntington's disease,
apparently doesn't want to know

527
00:43:36,000 --> 00:43:40,000
because if he learns that he's going
to get it he's just going to be

528
00:43:40,000 --> 00:43:44,000
depressed.  If he learns that he
didn't get it he might be relieved,

529
00:43:44,000 --> 00:43:48,000
but he doesn't want to take that
chance so he's just leading life in

530
00:43:48,000 --> 00:43:52,000
hopes that he doesn't have the
disease allele.

531
00:43:52,000 --> 00:43:56,000
Now, I actually don't know in his
case whether he has children or not.

532
00:43:56,000 --> 00:44:00,000
He has children, so he actually
made that decision almost for his

533
00:44:00,000 --> 00:44:04,000
children as well.
So important implications for these

534
00:44:04,000 --> 00:44:09,000
kinds of genetic diseases.
Now, here's an interesting pattern

535
00:44:09,000 --> 00:44:14,000
that I want to share with you.
And this relates to a phenomenon

536
00:44:14,000 --> 00:44:30,000
called penetrance.

537
00:44:30,000 --> 00:44:34,000
Penetrance.  Penetrance is a number
which reflects the percentage of

538
00:44:34,000 --> 00:44:38,000
individuals who have the disease
genotype who end up getting the

539
00:44:38,000 --> 00:44:43,000
disease.  I've been telling you
about examples where that's 100%.

540
00:44:43,000 --> 00:44:47,000
If you have the disease genotype
you get the disease.

541
00:44:47,000 --> 00:44:51,000
But that's not always true.
Sometimes you can have the disease

542
00:44:51,000 --> 00:44:56,000
genotype, but because of other
factors like environmental factors,

543
00:44:56,000 --> 00:45:00,000
what you eat, what you get exposed
to you actually don't

544
00:45:00,000 --> 00:45:05,000
develop the disease.
Or maybe you just got lucky because

545
00:45:05,000 --> 00:45:09,000
some of these diseases are
stochastic in nature.

546
00:45:09,000 --> 00:45:13,000
And you might have been one of the
lucky ones.  That would be an

547
00:45:13,000 --> 00:45:17,000
example of lack of penetrance.
You have the disease genotype but

548
00:45:17,000 --> 00:45:21,000
you don't have the disease itself.
And this can lead to the

549
00:45:21,000 --> 00:45:25,000
development of individuals in
pedigrees, such as the one I'm going

550
00:45:25,000 --> 00:45:30,000
to show you, who are obligate
carriers, obligate carriers.

551
00:45:30,000 --> 00:45:34,000
We call them obligate carriers
because they have a child who is

552
00:45:34,000 --> 00:45:39,000
affected but they themselves were
not affected.  And they have a

553
00:45:39,000 --> 00:45:43,000
parent who likewise was affected.
So the simplest explanation for a

554
00:45:43,000 --> 00:45:48,000
pedigree such as this is that this
mother passed along the disease

555
00:45:48,000 --> 00:45:52,000
allele to her daughter but she did
not manifest the disease,

556
00:45:52,000 --> 00:45:57,000
an example of lack of penetrance,
but she still had the disease allele

557
00:45:57,000 --> 00:46:02,000
which she passed onto her daughter
who developed disease.

558
00:46:02,000 --> 00:46:05,000
OK?  And we call these individuals
obligate carriers.

559
00:46:05,000 --> 00:46:09,000
Even though they don't manifest the
disease they must be carriers.

560
00:46:09,000 --> 00:46:12,000
And in that sense this circle
should be shaded.

561
00:46:12,000 --> 00:46:16,000
We haven't shaded it because
actually there are other

562
00:46:16,000 --> 00:46:20,000
explanations for how you can get
this pattern.  Sometimes,

563
00:46:20,000 --> 00:46:23,000
for example, the disease is such
that there are non-familial forms of

564
00:46:23,000 --> 00:46:27,000
the disease which complicate the
analysis.  Heart disease is a good

565
00:46:27,000 --> 00:46:31,000
example.  There are familial forms
of heart disease and there is

566
00:46:31,000 --> 00:46:34,000
sporadic heart disease.
Maybe this woman doesn't have the

567
00:46:34,000 --> 00:46:38,000
predisposing mutation and her
daughter just developed heart

568
00:46:38,000 --> 00:46:42,000
disease.  That can happen.
Another example is that maybe she

569
00:46:42,000 --> 00:46:45,000
picked up a new mutation.
Her mother is actually clean but

570
00:46:45,000 --> 00:46:49,000
she picked up her own mutation in
the development of the sperm or egg

571
00:46:49,000 --> 00:46:53,000
that gave rise to her,
and then she has the disease.

572
00:46:53,000 --> 00:46:57,000
That would be rare but not
unprecedented.

573
00:46:57,000 --> 00:47:01,000
And the final example,
which is the most interesting,

574
00:47:01,000 --> 00:47:05,000
is so-called non-paternity or even
non-maternity.

575
00:47:05,000 --> 00:47:09,000
So we're making an assumption here
based on what the family has

576
00:47:09,000 --> 00:47:13,000
provided us in terms of this
pedigree that this girl is the

577
00:47:13,000 --> 00:47:17,000
daughter of this mating,
this woman and this man.  But about

578
00:47:17,000 --> 00:47:21,000
10% of kids born in this country
actually have a father who isn't

579
00:47:21,000 --> 00:47:25,000
their father.  It's a shocking
statistic, I know,

580
00:47:25,000 --> 00:47:29,000
but it's true.  This is called
non-paternity.

581
00:47:29,000 --> 00:47:34,000
So it might be the case that this
woman actually doesn't have the

582
00:47:34,000 --> 00:47:40,000
mutation.  It's just that her father,
her mate, the father of this girl

583
00:47:40,000 --> 00:47:45,000
[LAUGHTER] is not that guy.
And this is sick but true, most

584
00:47:45,000 --> 00:47:51,000
often in situations like this it's
Uncle Bob or brother Steve.

585
00:47:51,000 --> 00:47:57,000
I know it's disgusting but this is
often an example,

586
00:47:57,000 --> 00:48:03,000
the explanation for examples such as
this.

587
00:48:03,000 --> 00:48:07,000
And another interesting example is
non-maternity.

588
00:48:07,000 --> 00:48:12,000
We're assuming that this is the
mother of this child but sometimes

589
00:48:12,000 --> 00:48:16,000
families don't want to admit,
for example, that this girl had a

590
00:48:16,000 --> 00:48:21,000
baby.  And so they give it to Aunt
Sue.  And now Aunt Sue's child gets

591
00:48:21,000 --> 00:48:25,000
the disease, but it's not because of
Aunt Sue's genes.

592
00:48:25,000 --> 00:48:30,000
It's because of her cousin.
OK?  So here are some examples.

593
00:48:30,000 --> 00:48:33,000
Now, I have one more minute,
and I need to riffle through the

594
00:48:33,000 --> 00:48:37,000
slides because I'm going to leave
you for a few days.

595
00:48:37,000 --> 00:48:40,000
And I want to just remind you that
there are X linked diseases that

596
00:48:40,000 --> 00:48:44,000
affect, that are both dominant and
recessive.  Most of them are

597
00:48:44,000 --> 00:48:48,000
recessive.  And here's a classic
example, an X linked recessive

598
00:48:48,000 --> 00:48:51,000
disease involving hemophilia in the
royal families of Europe.

599
00:48:51,000 --> 00:48:55,000
Importantly, when you look at X
linked disease pedigrees,

600
00:48:55,000 --> 00:48:58,000
and here's Duchenne muscular
dystrophy, another familiar disease,

601
00:48:58,000 --> 00:49:02,000
again X linked recessive, there are
certain rules that dictate the

602
00:49:02,000 --> 00:49:06,000
development of the disease
over the generations.

603
00:49:06,000 --> 00:49:10,000
They're summarized here.
And you should look in your book

604
00:49:10,000 --> 00:49:15,000
for more information.
And, finally, there are rare

605
00:49:15,000 --> 00:49:19,000
examples of X linked dominant
diseases, and their rules of

606
00:49:19,000 --> 00:49:24,000
inheritance are somewhat different.
So you should familiarize yourself

607
00:49:24,000 --> 00:49:27,000
with X linked modes of inheritance.