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Homozygosity Mapping Using Pooled DNA

Val C. Sheffield¹

¹University of Iowa, Iowa City, Iowa

Publication Name:

Current Protocols in Human Genetics

Unit Number:

Unit 1.11

DOI:

10.1002/0471142905.hg0111s13

Online Posting Date:

May, 2001

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Abstract

Genomic screening is a common and popular method for localizing human disease genes. Genotyping each individual sample can be a laborintensive and expensive process. This unit describes the technique of pooling DNA from many related affected individuals, genotyping the resulting pools, and scoring the results. This technique can greatly reduce the effort required to screen for genetic linkage and is particularly useful when applied to inbred populations. The unit includes a table showing a pool of human STRP markers developed by the Cooperative Human Linkage Center.

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Unit Introduction
Key Concepts
Basic Protocol: Amplification and Analysis of Pooled DNA
Reagents and solution
Commentary
Literature Cited
Figures
Tables

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Materials

Basic Protocol: Amplification and Analysis of Pooled DNA

Materials

Individual DNA samples from affected and unaffected (control) individuals
TE buffer, pH 7.4 (appendix 2D)

Primers for short tandem repeat polymorphic markers (STRPs; Research Genetics; see Table 1.11.1)

Table 1.11.1 STRP Markers for Genotyping Pooled DNA^a

Chromosome	Marker	Locus	Size range (bp)

1	ATA20F08	D1S1622	252-270

1	GATA29A05	D2S1368	179-207

1	GGAA3A07	D1S1612	98-127



1	GATA64G10	D1S1669	384-392

1	GATA27E01	D1S1597	162-178



1	GATA4A09	D1S547	286-306

1	GATA61A06	D1S1665	221-237

1	GATA109	D1S1728	159-167



1	GGAA23C07	D1S1678	297-309

1	GGAA20F08	D1S1675	225-253

1	GATA6A05	D1S551	173-185



1	GATA72H07	D1S2134	259-295

1	GATA12A07	D1S534	197-211

1	ATA29D04	D1S1631	131-155



1	GATA65H06	D1S2130	246-266

1	GGAA22G10	D1S1677	191-219

1	ATA2E04	D1S1588	118-135





1	GATA25B02	D1S1595	255-280

1	ATA4E02	D1S1589	201-214

1	GGAA5F09	D1S1679	142-163



1	GATA50F12	D1S1663	409-417

1	GATA48B01	D1S1660	226-246

1	GATA44E05	D1S1656	128-168



1	GGAT2A07	D1S552	244-256

1	GATA50F11	D1S1609	177-205



1	GATA87F04	D1S2141	236-264

1	GATA4H09	D1S549	164-184



1	ATA29C07	D1S3462	256-271

1	GATA7C01	D1S518	188-212



2	GATA72G11	D2S1780	312-336

2	GATA8F07	D2S405	240-256

2	GAAT1A5	D2S423	112-124



2	GATA12H10	D2S427	250-258

2	GATA71G04	D2S1777	195-207

2	GGAA20G10	D2S1400	114-122

2	ATA4F03	D2S1356	237-246

2	GATA69E12	D2S1394	161-177

2	ATA27D04	D2S1352	114-129



2	GATA88G05	D2S1790	281-325

2	GATA5G02	D2S436	178-190

2	GATA65C03	D2S1391	113-137



2	GATA71D01	D2S1776	288-312

2	GATA8H05	D2S442	200-204

2	GATA8F03	D2S441	134-150



2	GATA4G12	D2S434	262-274

2	GATA23D03	D2S1363	171-191

2	GATA52A04	D2S1384	140-156



2	GATA26B04	D2S1326	238-266

2	GATA4E11	D2S410	164-178

2	GATA30E06	D1S1649	108-136



3	GGAA4B09	D3S2403	252-264

3	GATA22G12	D3S2387	180-202

3	ATA10H11	D3S2409	118-127



3	GGAT2G03	D3S2406	314-348

3	GATA88H04	D3S1050	228-248

3	GATA27C08	D3S2432	144-156



3	GATA3H01	D3S1763	264-272

3	GATA73D01	D3S3038	188-232



3	GGAA16E09	D3S2465	312-328

3	ATA28H11	D3S4009	240-250

3	GATA32D12	D3S2436	164-180



3	GATA6G12	D3S2398	270-286

3	GATA84B12	D3S3045	177-201

3	ATA22E01	D3S2418	97-115



3	GATA6F06	D3S1766	210-218

3	GATA68F07	D3S2460	144-172



3	GATA22F11	D3S2427	218-238

3	GATA3C02	D3S1744	138-154



4	GATA25B06	D4S2408	265-275

4	GATA7D01	D4S1627	183-198

4	GATA22G05	D4S2366	121-145

4	GATA27G03	D4S2368	307-328

4	GATA28F03	D4S3248	238-254

4	GATA90B10	D4S2639	165-193



4	GATA42H02	D4S2417	254-274

4	GATA11E09	D4S1644	194-202

4	ATA27C07	D4S2397	133-145



4	GATA107	D4S1625	186-202

4	GATA24H01	D4S2367	137-145



4	ATA26B08	D4S2394	241-259

4	GATA10G07	D4S3243	161-169



4	GATA62A12	D4S2623	205-242

4	GATA2F11	D4S1647	131-151



4	GGAA19H07	D4S2431	234-246

4	GATA8A05	D4S1629	139-151



5	GATA84E11	D5S2505	261-297

5	GATA3A04	D5S807	166-202

5	GATA31H11	D5S1492	119-123



5	GGAA11C04	D5S1473	246-262

5	GATA7C06	D5S1470	177-199

5	GATA52A12	D5S1501	99-113



5	GATA68A03	D5S2501	310-338

5	GATA62A04	D5S1505	238-270

5	GATA32A11	D5S2494	153-185



5	GATA3E10	D5S817	260-272

5	GATA6E05	D5S820	194-202



5	GATA2H09	D5S816	222-250

5	GATA67D03	D5S2500	149-181

5	GATA69H12	D5S1719	86-110



5	ATA23A10	D5S1480	218-239

5	GATA7H10	D5S1471	156-172



5	GATA3H06	D5S1462	186-198

5	ATA4D10	D5S1453	142-163



6	GATA29C09	D6S1960	272-292

6	GTAT1H06	D6S1019	224-234

6	GGAT3H10	D6S1017	153-173

6	ATA28B11	D6S1031	250-265

6	GATA89B07	D6S1281	176-208

6	GATA112F02	D6S1270	114-138



6	GATA68H04	D6S1056	242-270

6	ATC4D09	D6S1006	194-200

6	ATA11D10	D6S1021	142-157



6	GATA22G09	D6S1007	288-296

6	GATA3H05	D6S477	210-230

6	GATA31	D6S474	151-167



6	GATA23F08	D6S1040	271-283

6	GATA52D05	D6S1050	176-204

6	ATA22G07	D6S1027	117-138



6	GATA64D02	D6S1053	291-319

6	GGAA8D08	D6S503	246-262

6	GATA85F06	D6S1280	170-190



7	GGAA3F06	D7S1808	240-254

7	GATA41G07	D7S1802	180-200

7	GATA61G06	D7S2201	104-120

7	GATA73D10	D7S2204	214-268

7	GATA13G11	D7S817	157-167



7	GATA5D08	D7S821	238-270

7	GATA31A10	D7S2846	172-196



7	GATA4H10	D7S1805	196-212

7	GATA45E12	D7S1826	144-164



7	GATA43C11	D7S1804	244-280

7	GATA32C12	D7S1824	166-190



8	ATA3A02	D8S1099	250-259

8	ATC2D12	D8S1100	192-195

8	GATA23D06	D8S1106	138-148



8	GGAA23E06	D8S1990	368-388

8	GATA21C12	D8S1128	242-262

8	GATA7G07	D8S1179	168-190



8	GGAA8G07	D8S1113	217-241

8	GGAA20C10	D8S1477	140-180



8	GATA72C10	D8S1145	262-290

8	GATA25C10	D8S1130	137-157



8	GATA12B06	D9S920	276-288

8	ATA19G07	D8S1119	175-196

8	GAAT1A4	—^b	140-160



8	GATA41A01	D8S1136	245-261

8	GATA26E03	D8S1132	143-159



8	GATA8G10	D8S1110	259-275

8	GATA6B02	D8S592	148-156



9	GATA62F03	D4S2624^c	284-296

9	GATA7D12	D9S301	204-230

9	GATA71E08	D9S1118	142-178



9	GGAA22E01	D9S938	383-419

9	GATA4D10	D9S302	256-304



9	GATA21F05	D9S689	252-268

9	GATA27A11	D9S925	171-194

9	ATA18A07	D9S910	106-133

9	GATA48D07	D9S930	277-301

9	GATA64G07	D9S934	206-230



10	GATA6E06	D10S674	226-242

10	ATA31G11	D10S1412	153-168



10	GATA70E11	D10S1423	219-243

10	GATA73E11	D10S1426	157-169



10	ATA20B07	D10S1220	231-243

10	ATA24F10	D10S1225	181-193

10	ATA29C03	D10S1230	120-135



10	ATA24A05	D10S1223	272-293

10	GGAA2F11	D10S677	198-222

10	GGAA5D10	D10S1213	99-119



10	GATA48G07	D10S1237	400-432

10	GATA88F09	D10S1435	260-276

10	GATA64A09	D10S1239	162-186



10	GGAT1A4	D10S2327	204-224

10	GAAT5F06	D10S2325	135-143

11	ATA33B03	D11S2362	212-233

11	GATA48E02	D11S1981	147-175



11	GGAA7G08	D11S1986	188-240

11	GATA23F06	D11S1999	109-134



11	GGAA5C04	D11S1985	240-280

11	ATA34E08	—^b	157-169



11	GATA64D03	D11S4464	228-252

11	GATA6B09	D11S1392	203-211

11	GATA23E06	D11S1998	149-157



11	GATA30G01	D11S2002	223-251

11	GGAA17G05	D11S1984	177-197



12	GATA7F09	D12S374	276-292

12	GATA4H03	D12S372	174-190

12	ATA27A06	D12S1042	119-140



12	GATA6C01	D12S373	209-225

12	GATA26D02	D12S1052	153-164

12	ATA25F09	D12S2070	89-107

12	GATA32F05	D12S2078	254-278

12	GGAT2G06	D12S398	117-137



12	GATA63D12	D12S1064	172-196

12	GATA85A04	D12S1300	112-136



12	GATA11H08	D12S391	221-241

12	GATA13D05	D12S392	139-148



12	GATA4H01	D12S395	222-238

12	GATA3F02	D12S375	165-189



13	GATA64F08	D13S800	293-309

13	GGAA29H03	D13S1493	212-252

13	GATA51B02	D13S796	149-169



13	GATA43H03	D13S793	249-269

13	ATA26D07	D13S779	182-200



13	GATA23C03	D13S787	253-261

13	GATA7G10	D13S317	178-198





14	GATA74E02	D14S742	395-415

14	GATA31B09	D14S1280	292-304

14	ATA25E04	D14S597	178-193



14	GGAA10C09	D14S587	254-274

14	GATA4B04	D14S306	194-208

14	GATA5H04	D14S297	96-112



14	GATA51E09	D14S610	360-376

14	ATA19H08	D14S592	227-239

14	GGAA4A12	D14S588	117-129



14	GATA30A03	D14S606	265-277

14	GGAA21G11	D14S617	143-175



15	ATA24A08	D15S652	288-306

15	GATA63A03	D15S659	174-210



15	GATA22F01	D15S657	336-348

15	GATA27A03	D15S642	197-213

15	GATA73F01	D15S816	130-150



15	ATA24D04	D15S653	296-314

15	GATA50G06	D15S643	207-223

15	GATA81F03	D15S817	149-173

16	GGAA3G05	D16S753	250-270

16	ATA3A07	D16S748	187-208

16	GATA81D12	D16S2624	137-153



16	GGAA23C09	D16S771	247-271

16	GATA22F09	D16S3253	177-184



16	GATA71H05	D16S769	263-275

16	GATA62G05	D16S2619	143-163



17	GTAT1A05	D17S1308	304-316

17	GAAT2C03	D17S1298	246-254

17	GATA25A04	D17S1299	190-202



17	GGAA9D03	D17S1294	252-264

17	GATA10H07	D17S969	130-138



17	GGAA7D11	D17S1293	260-290

17	GATA8C04	D17S974	209-217

17	GATA28D11	D17S1301	151-163



17	GATA31B11	D17S2059	243-268

17	GATA49C09	D17S1290	172-208





18	GATA6D09	D18S851	250-266

18	ATA23G05	D18S858	196-208

18	GATA13	D18S535	131-155



18	GATA26C03	D18S1270	280-292

18	GATA11A06	D18S542	182-194

18	GATA64H04	D18S877	120-144



18	GATA10A09	D18S541	269-283

18	ATA1H06	D18S844	184-196



19	GATA66B04	D19S714	225-257

19	GATA29B01	D19S589	162-182



19	GAAA1B03	D19S601	210-224



19	GGAA2A03	D19S433	190-210



19	GATA21G05	D19S1034	216-232



20	GATA47F05	D20S481	220-248

20	ATA21E04	D20S473	180-186





20	GGAA7E02	D20S470	260-302

20	GATA46C01	D20S1085	179-193

20	GATA81E09	D20S604	125-158



20	GATA29F06	D20S477	242-262



21	GATA70B08	D21S1446	210-225

21	GATA11C12	D21S1432	128-144



20	GATA42A03	D20S478	252-276

22	GATA6F05	D22S685	172-197

22	GGAT3C10	D22S445	110-130



22	GATA21F03	D22S689	202-230

21	GGAA3C07	D21S1437	119-143



7	GATA3F01	D7S820	210-222

2	GATA11H10	D2S1360	140-176



14	UT562	D14S118	248-274

2	GATA86E02	D2S1788	183-207



8	UT721	D8S373	194-218

2	GATA27A12	D2S1328	156-164

7	GATA4E04	D7S1830	212-220

2	GGAA20G04	D2S1399	134-170



5	GATA11A11	D5S1456	194-206

2	ATA27H09	D2S1353	141-165



6	GATA32B03	D6S1009	239-278

3	GATA68D03	D3S2459	177-205



3	GATA92B06	D3S3053	226-238

3	GATA8B05	D3S1768	194-198

4	GATA5B02	D4S1652	137-149



9	ATA25F10	D9S915	195-216

4	ATA2A03	D4S2361	152-158



6	ATA1F08	D6S1003	298-316

3	GATA4A10	D3S1764	228-248

7	GATA23F05	D7S1799	174-182



11	GATA28D01	D11S2000	204-244

14	GATA51F04	D14S611	157-173

16	GATA73G05	D16S2622	75-87



12	PAH	PAH	229-257

7	GATA44F09	D7S2847	176-204



6	GATA81B01	D6S1277	282-314

9	GATA21A06	D9S921	175-229



17	GATA64B04	D17S1303	225-245

7	GATA24D12	D7S1818	183-199



11	ATA27C09	D11S2359	206-221

16	GATA11C06	D16S539	152-158

12	ATA29A06	D12S1045	80-104



7	GATA112F07	D7S2195	237-297

9	GATA89A11	D9S1122	191-211



13	GATA6B07	D13S325	202-218

21	ATA27F01	D21S1440	158-167



12	GATA5A09	D12S1090	218-258

14	GATA91G06	D14S749	160-184



19	GGAT2H06	—^b	211-223

18	ACT1A01	D18S843	180-189

19	GATA23B01	D19S586	232-244

21	GATA49E01	D21S1435	163-187



7	GATA119B03	D7S3047	170-186

1	GATA22D12	D1S1594	118-131



9	GATA12C06	D9S319	162-179

2	GAAT3C11	D2S2949 and D2S1359	128-136



14	ATA4B10	D14S580	205-223

4	GAAT1D1	D4S2362	144-152



9	ATA3H11	D8S569	198-204

6	ATA6B05	D6S1034	125-147



7	GATA30D09	D7S3058	210-242

6	ATA6C09	D6S1035	135-153



10	ATA10G07	D10S1218	213-231

9	GAAT1C06	D9S905	297-301



8	GATA31A06	D8S1989	224-244

11	GATA72A01	D11S2367	145-161



10	GGAA23C05	D10S1248	241-265

13	GGAA22G01	D13S895	161-181

15	GTAT1B2	D15S231	110-114



15	ATA24A06	D15S651	232-244

16	GATA86C08	D16S2625	171-191



5	ATA20G07	D5S2488	228-246

16	GAAT1E9	D16S749	136-144



17	ATA1H07	D17S1288	163-197

16	GAAT2B10	D167750	115-119



20	ACT1A04	D20S468	195-209

17	ATC6A06	D22S686	118-130



22	GGAA10F06	D22S686	180-208

18	ATA7D07	D18S1357	127-138



19	GATA66B01	D19S594	212-220

20	GATA86F01	D20S606	147-163



19	GATA84G04	—^b	340-380

9	GATA11A07	D9S318	270-290

7	GATA87D11	D7S2212	197-217

19	ATA9A06	—^b	223-229

10	GATA87G01	D10S1432	165-181



1	GATA68D01	—^b	243-251

11	GATA90D07	D11S2371	190-214



15	GATA88H02	D15S822	255-303

12	GATA73H09	D12S1294	177-209



3	GGAA22B10	D3S3054	378-398

20	GATA72E11	D20S602	276-288

18	GATA88A12	D18S976	172-200



22	ATA2G02	D22S1266	245-260

21	GATA8G04	D21S1270	186-194



3	GATA52H09	D3S2454	248-260

22	GATA11B12	D22S683	168-200

^a Markers were developed by the Cooperative Human Linkage Center and are grouped into sets than can be coamplified.

^b No D number has been assigned.

^c This marker has been mapped to chromosome 9 using radiation hybrids.

10× stock amplification buffer (see recipe)
2.0 mM 4dNTP mixture (appendix 2D)
5 U/µl Taq DNA polymerase
Light mineral oil
Formamide loading buffer (appendix 2D)
Rain-X (UNELKO) or Sigmacote (Sigma)
Binding solution (see recipe)
96-well microtiter plate for use in thermal cycler, or 0.5-ml microcentrifuge tubes
Thermal cycler, preferably accommodating 96-well microtiter plates
Equipment for denaturing polyacrylamide gel electrophoresis: e.g., Life Sciences Model S2 sequencing-gel apparatus
Water bath or heat block, 95°C
Additional reagents for quantifying DNA by absorption spectroscopy (appendix 3D), PCR amplification of SSLPs (STRPs; unit 2.5), denaturing polyacrylamide gel electrophoresis (appendix 3F), and silver staining of gels (unit 2.5)

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Figures

Figure 1.11.1

Flow chart for homozygosity mapping of recessive disease genes with short tandem repeat polymorphic markers (STRPs) using pooled DNA.

View Image
Figure 1.11.2

Example of an inbred pedigree and expected gel pattern (schematic drawing) for an STRP linked to an autosomal recessive disorder. N, normal individual; A, affected individual.

View Image
Figure 1.11.3

Example of an inbred pedigree and expected gel pattern (schematic drawing) for an STRP not linked to an autosomal recessive disorder. N, normal individual; A, affected individual.

View Image
Figure 1.11.4

Example of an actual silver-stained electrophoretic gel showing two STRPs linked to a recessive disorder. The two pools contained DNA from eleven affected individuals (lane A) and eleven normal controls (N). The individuals were part of an inbred kindred consisting of three related nuclear families.

View Image

Literature Cited

Literature Cited
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	Bassam, B.J., Caetano-Anolles, G., and Gresshoff, P.M. 1991. Fast and sensitive silver staining of DNA in polyacrylamide gels. Anal. Biochem. 196:80-83.
	Bateson, W. 1902. Mendel's Principles of Heredity. Cambridge University Press, Cambridge.
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