Molecular Photofitting (eBook)

Predicting Ancestry and Phenotype Using DNA

Tony Frudakis Ph.D. (Autor)

eBook Download: EPUB

2010 | 1. Auflage
712 Seiten
Elsevier Science (Verlag)
978-0-08-055137-1 (ISBN)

Infos

In the field of forensics, there is a critical need for genetic tests that can function in a predictive or inferential sense, before suspects have been identified, and/or for crimes for which DNA evidence exists but eye-witnesses do not. Molecular Photofitting fills this need by describing the process of generating a physical description of an individual from the analysis of his or her DNA. The molecular photofitting process has been used to assist with the identification of remains and to guide criminal investigations toward certain individuals within the sphere of prior suspects.

Molecular Photofitting provides an accessible roadmap for both the forensic scientist hoping to make use of the new tests becoming available, and for the human genetic researcher working to discover the panels of markers that comprise these tests. By implementing population structure as a practical forensics and clinical genomics tool, Molecular Photofitting serves to redefine the way science and history look at ancestry and genetics, and shows how these tools can be used to maximize the efficacy of our criminal justice system.

* Explains how physical descriptions of individuals can be generated using only their DNA
* Contains case studies that show how this new forensic technology is used in practical application
* Includes over 100 diagrams, tables, and photos to illustrate and outline complex concepts

Inhalt

Front Cover 1
Molecular Photofitting 4
Copyright Page 5
Table of Contents 6
Foreword 12
Preface 14
Acknowledgments 16
Chapter 1: Forensic DNA Analysis: From Modest Beginnings to Molecular Photofitting, Genics, Genetics, Genomics, and the Pertinent Population Genetics Principles 17
Part I: Introduction: Brief History of DNA in Forensic Sciences 17
The Statistics of Forensic DNA Analysis 22
The Nature of Human Genetic Variation 26
Population Genetics and Population Genomics 27
The Promise of Molecular Photofitting as a Tool in Forensic Science 32
Part II: The Basic Principles 35
Lack of Human Diversity Relative to Other Species 48
Chapter 2: Ancestry and Admixture 51
What Are Ancestry and Admixture? 51
The Need for Molecular Tests for Ancestry 53
Ancestry Informative Markers 59
Biogeographical Ancestry Admixture as a Tool for Forensics and Physical Profiling 70
Chapter 3: Biogeographical Ancestry Admixture Estimation-Theoretical Considerations 73
Estimating by Anthropometric Trait Value 73
Admixture and Gene Flow Estimated from Single Loci 75
Admixture in Individual Samples 84
Using the Hanis Method on Population Models k> 2
Parameter Uncertainty 91
Bayesian Methods for Accommodating Parameter Uncertainty 100
Sampling Error 104
Assumptions about Marker Linkage and Intensity of Admixture in Parents 106
Pritchard’s Structure Program 108
In Defense of a Simple Admixture Model 110
Practical Considerations for Building an Ancestry Admixture Test 111
Selecting AIMs from the Genome-How Many Are Needed? 119
Comparing the Power of Specific Loci for Specific Resolutions 126
Genomic Coverage of AIMs 130
More Elaborate Methods of Selecting Markers for Information Content 131
Shannon Information 132
Fischerian Information Content 134
Informativeness for Assignment 135
Type of Polymorphisms 139
Interpretation of Ancestry Estimates 141
Objective Interpretation 148
Genetic Mapping and Admixture 149
Appendix (Ancestry Frequency Table) 153
Chapter 4: Biogeographical Ancestry Admixture Estimation-Practicality and Application 161
The Distribution of Human Genetic Variability and Choice of Population Model 162
Marker Selection 179
Sample Collection 180
Presenting Individual Biogeographical Ancestry (BGAA) Results 195
Conceptual Issues 206
Chapter 5: Characterizing Admixture Panels 219
Parental Sample Plots 219
Model Choices and Dimensionality 221
Size of Confidence Contours 226
Repeatability 229
Sensitivity 236
Analysis of Results for Genealogists 238
Analysis of Results for Nongenealogists 246
Blind Challenge of Concordance with Self-Assessed Race 248
Confidence Interval Warping 251
Sampled Pedigrees 253
Simulated Pedigrees 256
Comparing Different Algorithms with the Same AIM Panel 257
Analysis Using Subsets of Markers 259
Resolving Sample Mixtures 261
Sample Quantity 266
Nonhuman DNA 267
Performance with Altered Parental Allele Frequencies 269
Correlation with Anthropometric Phenotypes 273
Simulations 276
Creating Simulated Samples 278
Source of Error Measured with Simulations 279
Relationship between Error in Populations and within Individuals 281
Precision of the 71 AIM Panel from Simulations 284
Trends in Bias from the 71 AIM Panel 286
95% Confidence Threshold for 71 AIM Panel 289
Precision of the 171 AIM Panel from Simulations 291
MLE Thresholds for Assumption of Bona Fide Affiliation 293
Comparison of 71 and 171 AIM Panels 293
Observed and Expected Bias 293
What Do the Simulations Teach Us about Interpreting BGA Admixture Results? 295
Bias Symmetry 296
Impact of MLE Algorithm Dimensionality 298
Simulations of Admixed Individuals 300
MLE Precision from the Triangle Plots 301
Confidence of Nonzero Affiliation 302
Standard Deviation from Confidence Intervals 302
Testing the Relation between Confidence Measures in Individuals and Populations 304
Space outside the Triangle Plot 305
Combined Sources Suggest an Average Error 310
Chapter 6: Apportionment of Autosomal Diversity With Continental Markers 313
The Need for Population Databases-Words Mean Less Than Data 313
Trends on an Ethnic Level: Autosomal Versus Sex Chromosome Pattern 315
What Do Continental Ancestry AIMs Say about Ethnicity? 319
The Significance of Fractional Affiliation Results on a Population Level 321
Reconstructing Human Histories from Autosomal Admixture Results 326
Shared Recent Ancestry Versus Admixture: What Does Fractional Continental Affiliation for an Ethnic Group Mean? 327
Returning Briefly to the Naming Problem-Relevance for Interpreting the Apportionment of Autosomal Diversity 329
A Sampling of Ethnicities Using the 171 AIM Panel 332
Interpretation of Ancestry Profiles for Ethnic Populations 338
East Asian Admixture in the Middle East and South Asia 353
Resolution within Continents Based on the Four-Population Model 367
Interpretation of Continental BGA Results in Light of What We Have Learned from Application to Ethnic Populations 368
Appropriateness of a Four-Population Model 371
Do Allele Frequency Estimation Errors Account for the Secondary Affiliations in Ethnic Subpopulations? 373
Indications of Cryptic Population Structure 375
Chapter 7: Apportionment of Autosomal Diversity with Subcontinental Markers 377
Subpopulation AIMs and Ethnic Stratification 377
Within the European BGA Group-A Brief History of Europeans 379
How Do We Subdivide Europeans for Forensics Use? 382
Development of a Within-European AIM Panel 383
The Euro 1.0 AIM Panel for a Four-Population Subcontinental Model 385
Establishing the Optimal Parental Representatives 386
Blind Challenge with Ethnically Admixed European-American Samples 394
Population Isolates and Transplants 396
Correlations with Anthropometric Traits 400
Test Error 403
Hierarchical Nature of Euro 1.0-Prior Information Required 413
Euro 1.0 Pedigrees as an Aid to Interpreting Results 419
Euro 1.0-Interpretation of Variation within Groups 423
An Historical Perspective 426
More Detailed Subpopulation Stratifications—k = 7 428
What Do the Groups NOR1, NOR2 . . . Mean? 430
Evaluating the Results from the k = 7 European Model 432
Comparison with Previous Studies Based on Gene Markers 433
Comparison with Results from Other Studies 435
Blind Challenge of the k = 7 Model Results with Ethnic Samples 436
Correlation with Anthropometric Traits 439
Pedigrees 441
Substantial Variation in Admixture within Ethnic Groups 441
Alternative Styles for Estimating Ethnic Admixture 443
Chapter 8: Indirect Methods for Phenotype Inference 445
Estimates of Genomic Ancestry Allows for Inference of Certain Phenotypes 445
Phenotype Variation as a Function of Human Population History and Individual Ancestry 446
Sources of Phenotypic Variation 448
Empirical Observation of Admixture-Based Correlation Enables Generalization 454
Empiricism as a Tool for the Indirect Method of Molecular Photofitting 456
Reverse Facial Recognition Using Genomic Ancestry Estimates 466
Estimating Phenotype from 2D Digital Photographs 470
Estimating Phenotype from 3D Digital Photographs 472
Examples of Database Queries-Global Characteristics from Digital Photographs 474
Examples of Database Queries-Ethnic Descriptors and Geopolitical Affiliations 477
Variation and Parameterization of Database Observations 480
Can Social Construct Such as Race Be Inferred from DNA? 484
Indirect Approach Using Finer Population Models 488
Indirect Inference of Skin Pigmentation 493
Sources of the Ancestry-Skin Pigmentation Correlation 501
Can We Infer M Knowing Genomic Ancestry? 504
Inferences of Composite Characteristics 506
Why Not Use the Direct Method Instead? 506
Indirect Inference of Iris Pigmentation 507
Chapter 9: Direct Method of Phenotype Inference 513
Pigmentation 516
History of Pigmentation Research 519
The Genetics of Human Pigmentation-A Complex Puzzle 520
Biochemical Methods of Quantifying Pigment 523
Iris Color 529
Iris Color Phenotyping: The Need for a Thoughtful Approach 530
Making Iris Color Measurements 533
Population Surveys of Iris Melanin Index (IMI) Values 539
Relation of IMI to Self-Described Iris Color 540
History of Genetic Research on Iris Color 543
Recent History of Association Mapping Results 546
OCA2-The Primary Iris Color Gene 550
An Empirical OCA2-Based Classifier for the Inference of Iris Color 559
The Empirical Method of Direct Phenotype Inference 569
Case Reports 574
Hair Color 578
Skin Pigmentation 599
Final Considerations for the Direct Inference of Skin Pigmentation 612
Chapter 10: The First Case Studies of Molecular Photofitting 615
Case Reports 615
Louisiana Serial Killer Multiagency Homicide Task Force Investigation 615
Operation Minstead 619
The Boulder, Colorado Chase Case 623
Other Cases 623
Chapter 11: The Politics and Ethics of Genetic Ancestry Testing 625
Resistance 626
Articles-Insight into Public Reaction 629
Molecular Eyewitness: DNA Gets a Human Face 629
DNA Tests Offer Clues to Suspect’s Race 634
Concerns of the Defense-Minded 642
Concerns of the Prosecution-Minded 645
Resistance in the Scientific Community 648
Racism and Genetic Ancestry Testing 663
Racism and the Common Racist Mantra 664
The Data Does Not and Probably Cannot Support the Racist Viewpoint 668
Subjective Nature of the Word Intelligence 671
According to Nature, Diversity Is a Good Thing 672
Bibliography 677
Index 693

Textauszug

Chapter 1

Forensic DNA Analysis: From Modest Beginnings to Molecular Photofitting, Genics, Genetics, Genomics, and the Pertinent Population Genetics Principles

With an Introduction by, Mark D. Shriver

PART I: INTRODUCTION: BRIEF HISTORY OF DNA IN FORENSIC SCIENCES

The forensic analysis of DNA is one of the clear successes resulting from our rapidly increasing understanding of human genetics. Perhaps much of this success is because this particular application of the molecular genetic revolution is ultimately pragmatic and because the genetic information required for efforts such as the Combined DNA Index System (CODIS) and The Innocence Project (www.innocenceproject.org) are relatively simple. Although the requirements of DNA in these instances, namely individualization, are indeed, relatively simple, they are somewhat technical, especially for the reader unfamiliar with molecular methods or population genetics. They nonetheless provide an important framework for the bulk of the material presented in this book. Though they are important for the rest of our discussion in the book, in this chapter, we provide only a brief summary of the standard forensic DNA methods, because these are well documented in other recent texts (Budowle et al. 2000; Butler 2001; Rudin & Inman 2002).

Modern forensic DNA analysis began with Variable Number of Tandem Repeats (VNTR), or minisatellite techniques. First discovered in 1985 by Sir Alex Jeffreys, these probes, when hybridized to Southern blot membranes (see Box 1-A), produced highly variable banding patterns that are known as DNA fingerprints (Jeffreys et al. 1985). Underlying these complex multibanded patterns are a number of forms (alleles) of genetic loci that simultaneously appear in a given individual. The particular combinations of alleles in a given individual are highly specific, yet each is visible because they share a common DNA sequence motif that is recognized by the multilocus molecular probe through complementary base pairing. These multilocus probes are clearly very individualizing, but problematic when it comes to quantifying results. Some statistics can be calculated on multilocus data, but certain critical calculations cannot be made unless individual-locus genotype data are available. In answer to this need, a series of single-locus VNTR probe systems were developed, and these became standard in U.S. forensic labs from the late 1980s through the early 1990s.

Box 1-A

The Southern Blot is named after Edwin Southern, who developed this important first method for the analysis of DNA in 1975. This method takes advantage of several fundamental properties of DNA in order to assay genetic variation, generally called polymorphism. The first step is to isolate high molecular weight DNA, a process known as genomic DNA extraction. Next, the DNA is digested with a restriction enzyme, which makes double-stranded cuts in the DNA at every position where there is a particular base pair sequence. For example, the restriction enzyme, EcoRI, derived from the bacteria, Escherichia coli strain RY13, has the recognition sequence, GAATTC, and will cut the DNA at every position where there is a perfect copy of this sequence. Importantly, sequences that are close to this sequence (e.g., GATTTC) will not be recognized and cut by the enzyme. The restriction digestion functions to reduce the size of the genomic DNA in a systematic fashion, and originally evolved in the bacteria as a defense mechanism as the bacteria’s own genomic complement was protected at these sequences through the action of other enzymes.

After DNA extraction the DNA is generally a series of large fragments averaging 25,000 to 50,000 bp in length. Because of the immense size and complexity of the genome, the results of a restriction enzyme digestion are a huge mix of fragments from tens of base pairs to tens of thousands of base pairs. When these fragments are separated by size on agarose gels using the process known as electrophoresis, they form a heavy smear. Although it’s hard to tell by looking at these smears since all the fragments are running on top of each other, everyone has basically the same smear since all our DNA sequences are 99.9% identical. Places where the restriction patterns differ because of either changes in the sequence of the restriction sites (e.g., GAATTC → GATTTC) or the amount of DNA between two particular restriction sites are called Restriction Fragment Length Polymorphisms (RFLPs).

The key advancement of the Southern Blot was to facilitate the dissection of these restriction enzyme smears through the ability of DNA to denature (become single-stranded) and renature (go back to the double-stranded configuration), and to do so in a sequence-specific fashion such that only DNA fragments that have complementary sequences will hybridize or renature. The DNA in the gel is denatured using a highly basic solution and then transferred by capillary action, using stacks of paper towels onto a thin membrane, usually charged nylon. After binding the digested DNA permanently to the membrane, we can scan it by annealing short fragments of single-stranded DNA, called probes, which are labeled in such a way that we can detect their presence. The probes will anneal with DNA at locations on the genomic smear to which they have complete, or near complete complementarity depending on the stringency of the hybridization and wash conditions. Since the probes are radiolabeled or chemiluminescently labeled, the result is a banding pattern where the location of particular sequences on the genome emerge as blobs called bands. The lengths of the bands can be estimated as a function of the position to which they migrated on the gel relative to size standards which are run in adjacent lanes.

The single-locus forensic VNTR systems are highly informative, with each marker having tens to hundreds of alleles. At every locus each person has only two alleles, which together constitute the genotype, one received from the mother and one from the father. Given such a large number of alleles in the population, most genotypes are very rare. A standard analysis with single-locus VNTRs typically included six such single-locus VNTR markers, each run separately on a Southern blot gel. The data from the separate loci would then be combined into a single result expressing one of two outcomes:

■ Exclusion—the suspect and evidence samples do not match

■ When the genotypes match, a profile or match probability, which is an expression of the likelihood that the two samples matched by chance alone.

Exclusions are pretty intuitive since the lack of genetic match between the samples eliminates any chance that the suspect could have donated the evidence (baring the very rare occurrences of somatic mutation, chimerism and mosaicism, each cell in our bodies has identical DNA). This of course presumes careful lab procedures and an intact and unquestioned chain of evidentiary custody. Given a match, profile probabilities are also quite intuitive, being expressions of the chances or likelihood that a particular genotype exists in a population. Profile probabilities are essentially a means to express the statistical power of a set of makers to demonstrate exclusion. For example, consider that both the suspect and biological evidence have blood type AB, the least common ABO genotype in most populations. There is no exclusion, but does that mean the suspect left the sample? Since about 4% of people have the AB genotype we say that the profile probability is 0.04 and that given no other information, the chances of having a match by chance alone are 1 in 25. Another way to read this profile probability is to say that 4% of the people match the person who left the sample.

Maybe these are good betting odds in the casino, but in both science and in court where the destiny of human lives are at stake, more stringent criteria are required. For one thing, the frequency of 4% in the population does not necessarily mean there is a 1 in 25 chance that the suspect donated the evidence. When tests of such limited power were used, other forms of evidence that contribute to the prior probability the suspect donated the evidence would have to be taken into account. Generally, genetic markers are not the only evidence against the defendant and other pieces of information can be combined with the genetic data to comprise a preponderance of evidence. With DNA markers commonly used today, profile probabilities are much smaller than 4%, and thus the weight of the evidence is so great that convictions could be and sometimes are made solely on DNA results, without other evidence or prior probabilities taken into account.

Single-locus VNTRs were replaced by newer marker systems that became possible as a result of the Polymerase Chain Reaction (PCR), a process of amplifying DNA in vitro, which won a Nobel prize for its inventor, Kary Mullis. These newer markers are most commonly called Short Tandem Repeats (STRs) although they first were referred to as microsatellites since their repeat units are shorter than minisatellites. In many ways STRs are different from VNTRs. For example, STRs generally mutate one or two repeat units at a time and VNTRs mutate in steps of many repeats. There are a number of other differences and similarities in how these markers evolve and how they can be used but these are beyond the scope of this presentation, and interested readers should consult Goldstein and Schlotterer (1999).

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Produkt-Details

• Erscheint lt. Verlag: 19.7.2010
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber
• Themenwelt: Studium ► 2. Studienabschnitt (Klinik) ► Pathologie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Recht / Steuern ► Strafrecht ► Kriminologie
• Themenwelt: Sozialwissenschaften
• Themenwelt: Technik ► Bauwesen
• ISBN-10: 0-08-055137-8 / 0080551378
• ISBN-13: 978-0-08-055137-1 / 9780080551371